CN101321542A

CN101321542A - Microparticles for microarterial imaging and radiotherapy

Info

Publication number: CN101321542A
Application number: CNA2004800167911A
Authority: CN
Inventors: B·R·莱恩; D·A·范厄科; A·S·肯尼迪; H·甘德哈里; A·南
Original assignee: University of Maryland at Baltimore
Current assignee: University of Maryland at Baltimore
Priority date: 2003-06-20
Filing date: 2004-06-18
Publication date: 2008-12-10

Abstract

Microparticles comprising a core, at least one linking carrier on the core, and at least one radioactive therapeutic agent covalently bonded to the linking carrier. The radioactive therapeutic agent may be a radionuclide or a radiopharmaceutical. A method of radiation therapy of a patient by administering to the patient the microparticles. The treatment may be radiation therapy to treat cancer or a tumor. A kit for preparing a microparticle treatment and a method for using the kit to prepare a microparticle treatment dose. The microparticle treatment dose may be made at a location of administration or at a site proximate to the location of administration, such as a local radiopharmacy, laboratory, hospital or physician's office.

Description

Be used for microarterial imaging and radiocurable microparticle

The cross reference of related application

[01] the application requires on June 20th, 2003 to submit to, the U.S. Provisional Application 60/479 of " Instant Microparticles forMicroarterial Imaging and Radiotherapy " by name, 832 priority, this U.S. Provisional Application integral body is by reference incorporated this paper into.The application also requires on January 23rd, 2004 to submit to, the U. S. application 10/762 of " Microparticles for Microarterial Imaging and Radiotherapy " by name, 507 priority, this U. S. application integral body is by reference incorporated this paper into.

Background of invention

[02] there is every year the liver that surpasses 100,000 patients to suffer from preinvasive cancer (primary cancer) or metastatic cancer (metastatic cancer) in the U.S..Most patients has operation unresectable infringement (lesions), and these infringements are also very weak to chemotherapeutical reaction.Outside conventional planning treatment of transmitting can make liver neoplasm degenerate or destroyed, almost is impossible but will mainly carry out radiation to the tumor cell in the liver selectively.In addition, destroy the tolerance of the needed radiation dose of liver neoplasm considerably beyond the normal liver cell of next-door neighbour's tumor.Therefore, although radiation has great potentiality as important antitumour treatments, but be not overcome by the caused problem of the characteristic of this non-selectivity, thereby make radiotherapy not have effect, and/or make excessive radiation dose be applied on health tissues and the cell.The present invention treats cancerous cell, entity tumor and rheumatoid arthritis by fixed point internal radiation therapy (site-directed internal radiation therapy) is provided, thereby has overcome these limitation.

The treatment of hepatocarcinoma

[03] in the past decade, inculcate in the clinical trial of (hepatic artery infusion), dropped into ample resources, wherein normally FUDR or FU of chemotherapeutant at test chemotherapeutant Hepatic artery.(Kemeny?et?al.，New?England?Journal?of?Medicine?1999；341：2039-2048；Kennedy?et?al.，Proceedingsofthe?14th?International?Congress?on?Anti-Cancer?Treatment?2003：156；Kennedy?et?al.，Int?J?Cancer?2002；S13：226-227.)。

[04] although carried out 8 prospective random experiments in the patient who suffers from colorectal carcinoma hepatic metastases tumor, efficient of inculcating for this kind chemotherapy and best usage are failed the result that agrees.For other diseases, such as benign tumor, malignant tumor, breast carcinoma, pulmonary carcinoma and sarcoma, it is main means that hepatic injury is carried out non-operative treatment, and this short-term life continuation for survivor can produce best remission effect.Be realized already, chemical sensitization (chemosensitization) is useful concerning many entity tumors.Yet, not clear as how optimal mode transmit the liver radiation, consider the tolerance of normal structure simultaneously.The short distance treatment provides hope for the transmission cancerocidel dose.For diffusibility hepatocarcinoma or liver is taken place probably when outer depleted, avoid excision.In addition, exploring alternative method, such as radioactive seed displacement (radioactive seed placement), (Kennedy et al., Regulatory Peptides 2002 make progress in 3D external beam treatment plan (3D external beam treatment planning) prior to for it; 108:32.).

[05] known other topical therapeutic, such as the invasive minimum of radio-frequency ablation procedure, but just be applicable to seed source method for implantation (seed implant approach), in the tumor limited, kitchen range (focal tumors) just effectively.(Murthy?et?al.，J?Vasc?Interv?Radiol?2002；13：S2；Murthy?et?al.，Proceedingsof?American?Association?for?Cancer?Research?2002；43：485；Murthy?et?al.，J?VascInterv?Radiol?2002；13：S2；Sarfaraz?et?al.，International?Journal?of?Radiation?Biologyand?Physics?2001；51：32-33.)。

[06] although chemotherapy recently, operation and interventional radiology (interventional radiology) are obtained certain progress, the entity tumor in liver still remains in the remarkable and common position of refractory disease of entity tumor.Only the conservative estimation to the hepatopathy in the colorectal carcinoma shows, has 77,500 cases every year at least in the U.S..(Kemeny?et?al.，New?England?Journal?of?Medicine?1999；341：2039-2048.)。Cancer of pancreas, carcinoid tumor, gastric cancer and other entity tumors are also taken into account, and patient's sum of suffering from pernicious liver neoplasm surpasses 150,000 (Fong et al., CA Cancer J Clin 1995; 45:50-62).In addition, incidence rate in the U.S. and other local hepatocyte cancers (hepatocellular cancer) increases day by day, and 1991 between nineteen ninety-five, the speed of the U.S. is per 100,2.4 morbidities of 000 philtrum (El-Serag et al., N Engl J Med 1999; 340:745-50)].Unfortunately, the major part among these patients can not be carried out medical operating treatment (curativesurgical therapy), needs alternate Therapeutic Method.Although radiation therapy provides potential benefit for these patients, carry the radiation of enough high doses by external beam (external beam), destroy metastatic hepatic neoplasm or the constitutional liver tumor is normally unpractical, this is because hepatocyte has low relatively radiation hardness ability.In the initiative work that Lawrence carries out, the three-dimensional treatment of carrying out with common Hepatic artery chemotherapy (concurrent hepatic arterv chemotherapy) of suitable shape (conformal three-dimensional treatment) shows, when the radiating dosage range that gives is identical with the dosage range that is transported to non-liver site, produced the persistent control of liver neoplasm, and can not cause the liver function forfeiture.(Lawrence?et?al.，Oncology(Huntingt)1993；7：51-7；discussion?57-8，63；Lawrence?et?al.，Front?Radiat?Ther?Oncol?1996；29：221-8；Lawrence?et?al.，Int?J?Radiat?Oncol?Biol?Phys?1991；20：555-61；McGinn?et?al.，J?ClinOncol?1998；16：2246-52；McGinn?et?al.，Semin?Radiat?Oncol?1997；7：313-323.)。Yet most patient can not accept this or other topical therapeutic, such as radio-frequency ablation procedure, frigotherapy or chemoembolization method.Therefore, the technology that this area long-term needs are such, it can be transported to tumor specifically with radiation therapy dosage, does not injure normal, healthy perienchyma and cell simultaneously.A field that needs this type of invention especially is the treatment liver tumor.

[07] to form be such process to thromboembolism, wherein material injected blood vessel to the level that is full of to small part, or so that clog blood vessel and/or promote grumeleuse to form, and like this, the blood flow by blood vessel reduces or stops.For various medical reasons, the thromboembolism effect of blood vessel may be useful, comprises by cutting off blood supply preventing or controlling because of bleeding of causing of damage (for example the tissue bleeds, the intestines and stomach is hemorrhage, angiorrbagia with relevant with aneurysm hemorrhage) or excise diseased tissue (for example tumor, vascular malformation, hemorrhage etc.).Thromboembolism formation also can be used at intra-operative or just finish the loss of operation back prevention blood.Can before operation, carry out the thromboembolism effect, thereby shrink tumor size, help to see tumor, and prevent the blood relevant loss with operative procedure to tumor.

[08] no matter has or not radiation effects, can trace back to Prinzmetal (Van Echo et al., Amer Soc Clin Oncol 2001 the pioneering effort that vascular occlusive agent (vascular embolic agents) is done; 260a:1038.), Prinzmetal at first uses glass bead to inculcate (glass sphere infusion) by the tremulous pulse approach in the zooscopy of nineteen forty-seven and people's object.Soon subsequently, Muller uses radiogold intravenous, in charcoal to treat to suffer from both sides pulmonary carcinoma the patient of (bilateral lung cancer) in nineteen fifty-one.Also have, at the early stage multidigit researcher sixties in 20th century---they treat the high nervus vasculairs endocrine tumors (highlyvascular neuroendocrine tumor) in the liver---90 yttriums-resin balls of having reported about 35 μ m is carried out the efficient that the liver tremulous pulse is inculcated.Yet, to inculcate and produced fatal toxic level, this causes ulcer and hemorrhage relevant with spheroid under one's belt in deposition unintentionally.Other people have also described because of radiation-induced fatal pulmonary's toxicity, and this is because the radioactivity spheroid is shunted (shunt) to lung from liver, the adjacent capillary bed behind the liver.The polymeric microspheres that nearest research is used glass microspheres, resin spheroid and described herein shows that intestines and stomach (GI) is hemorrhage, gallbladder hardens or the toxic incidence rate of pulmonary is relatively little.(Burton?et?al.，1989；Anderson?et?al.，1992；Yan?etal.，1993；Andrews?et?al.，1994；Lau?et?al.，1994；Leung?et?al.，1994；Kennedy?et?al.，2001；Kennedy?et?al.，2002；Coldwell?et?al.，2001；Wright?et?al.，2002；Mourtzikos?et?al.，2002；Hisley?et?al.，2002；

et?al.，1999.)。

[09] early stage in the sixties in 20th century, attempt transmitting 90Y or the 32P that is attached on resin or the ceramic microspheres, in liver, use the β radiation.(Ariel?IM.，1965；Ariel?et?al.，1967；Simon?et?al.，1968；Caldarolaet?al.，1965；Blanchard?et?al.，1964；Blanchard?et?al.，1965；Kim?et?al.，1962.)。Yet because compared with other isotopes, isotope 90Y has high relatively β energy, trend afterwards is towards using the 90Y development.90Y ( ⁹⁰Y) be pure beta emitter, it decays into stable zirconium-90, and average energy is 0.94MeV, and the half-life is 2.67 days (64.2 hours).In commercial reactors, 90Y is by right ⁸⁹Y carries out neutron bombardment and produces, and produces ⁹⁰Y β radiation, tissue permeability are 2.5mm, and maximum magnitude is 1.1cm.A GBq's (27mCi) ⁹⁰Y transmits the accumulated dose of about 50Gy/Kg in tissue.

The radiological predication fallout plot granule

[10] previous effort is sent to the patient who suffers from cancer partly with radioactive substance, as a kind of form of radiation therapy.In some cases, radioactive substance is impregnated in (embedding) in granule, seed source (seeds), tinsel and similar relevant structure, and these structural materials are directly implanted cancer position (tumor).Radioactive substance also has been formulated into microsphere, is used for being injected into the arterial blood supply of Target organ.Radioactive grain or microsphere are imposed in the blood supply of Target organ, be called selectivity internal radiation treatment (Selective InternalRadiation Therapy (SIRT)).

[11] with respect to traditional external beam radiotherapy (external beam radiotherapy), SIRT has many potential advantages.At first, radiation preferentially is sent on the cancer of Target organ.Secondly, radiation is along with radionuclide decay slowly and constantly transmits.The 3rd, by using vasoactive agent, control arterial blood such as angiotensin-2 and supply with such as vasodilatin, can increase the percentage ratio of the radiological predication fallout plot spheroid that arrives the organ cancer location compared with the normal structure of health.The result is the radiation dose that has preferentially increased the cancer position, and the radiation dose with normal structure maintains quite low level simultaneously.(Burton，M.A.et?al.；1988.)。

[12] in the clinical practice the earliest of the microsphere that contains 90Y, yttrium is impregnated in (embedding) in polymeric matrix, and polymeric matrix is mixed with microsphere.Although these microsphere density are suitable, guarantee in liver, to have good distribution characteristics, the radioreagent 90Y seriously infiltrates from microsphere, and this has caused other non-destination organizations by radiation inadequately, just non-specific radiation.

[13] in a kind of trial that overcomes infiltration problem, such radiological predication fallout plot spheroid is disclosed, it comprises the biocompatible glass material, the biocompatible glass material include the β of uniform distribution (embedding) in glass-or γ-radiation radiosiotope such as 90Y, (International Patent Application WO 86/03124).In addition, these glass microspheres need carry out the neutron activation effect before using.

[14] generation of light polymer ions exchange microballoon body (polymeric ion exchange microspheres) has been developed when being used for solving in being injected into body the serious problems of the saturating filter of yttrium.When microsphere is injected into the liver tremulous pulse, for the secondary liver cancer patient obtained high target response rate (objective response rate) (Gray, B.N.etal.1992.).The shortcoming of this kind polymer ions exchange microballoon body is, stable yttrium-89 isotope is carried out the neutron activation effect after, the 90Y radionuclide must join in the microsphere.This just needs special facility, and operator are had danger.Also have, polymer ions exchange microballoon body only contains the yttrium of low percentage ratio, and this has influenced the dosage level that is used for administration unfriendly.

[15] the 90Y carrier is improved, it comprises the material based on resin and pottery.

Reported with Day glass (manganese borate lead glass, 25-32 μ m) microsphere has been improved, with rhenium (natural isotope ¹⁸⁶Re and ¹⁸⁷Re) replace 90Y.These have big cross section concerning neutron, more be easy to generate the beta emitter of treatment quantity ¹⁸⁶Re and ¹⁸⁸Re, it has the ceiling capacity of 1.1MeV and 2.1MeV respectively, and ⁹⁰That Y is 0.97MeV.Yet, use their effect to be, the gamma-radiation of release be 9.5% ( ¹⁸⁶Re) and 15% ( ¹⁸⁸Re).Report that they are used to suffer from the sprague-Dawley rat of Novikoff hepatocarcinoma, Novikoff hepatocarcinoma is chemically-resistant and radiocurable tumor.What is interesting is that the generation of gamma-radiation makes imaging become possibility, yet, compared with ⁹⁰Y (65 hours), ^186+188The half-life (17 hours) that Re is very short, make ^186+188Re is unfavorable for clinical practice.

[16] use solid glass radiological predication fallout plot spheroid has been reported in clinical research.For example, the treatment of usefulness solid glass radiological predication fallout plot spheroids such as Shepherd suffers from 10 patients of primary hepatoma, yet neither one demonstrates treatment and replys (Shepherd, F.et al., 1992.) among these patients.

[17] the radiological predication fallout plot spheroid (TheraSphere of clinical use

) (MDS Nordion, Inc., 447March Road, Ontario, Canada K2K 1X8) by being full of ⁹⁰The glass of Y is formed.The diameter of each spheroid is 25 ± 10 μ m, and like this, they mainly are hunted down in the terminal arteriole of tumor, and the terminal arteriole of tumor estimates that diameter is 8-10 μ m.Every milligram contains 22,000 to 73,000 microspheres according to estimates.In patient's body, ⁹⁰Y does not come out from the glass spheres diafiltration, and this is because they forever are captured in the substrate of microsphere.

[18] two kinds of products that can be used for microsphere treatment at present have significant deficiency.At first on spheroid, there is not the source (source) that can make it possible to carry out imaging in vivo and the spheroid position is identified.This also makes the effort of exploitation radiation therapy plan software (radiation treatment planning software) become complicated.Being extensive use of of clinical experiment and this kind equipment will require accurate dose calculating and location in liver, all be such for the current techniques of any short distance treatment product.The second, produce ⁹⁰The technology of Y spheroid is numerous and diverse, need load (shipment) from nuclear reactor, and this can delay a lot of times.Also have, with regard to maximal dose, output is limited.Therefore, need more effective production system, it will make more patient in time receive treatment.Because radioactive activity is to have fixed activity during fabrication, has only 4 hours time (window) for the treatment application of radioactive glass spheroid, and, be＜24 hours for the resin spheroid.

[19] non-operative treatment that carries out in out-patient department (outpatient setting) can be treated many patients safely, uses available guided Interventional Technique and conduit simultaneously.By the new treatment radiological predication fallout plot granule that can carry out the location specific treatment to tumor is provided, the present invention has satisfied the long-term needs in the radiation therapy.Microparticle of the present invention has utilized β-launch isotopic characteristic, and its permission is carried out local irradiation to a certain position such as tumor, and nearby the tissue dosage in zone significantly descends, thereby can not injure the normal cell that closes on.Recognize short distance electronics (short-range electrons) (providing by β-emission isotope) in any case can not be by imaging or be determined the position that gives behind the patient them such as those, therefore, in some embodiment of needs diagnosis of the present invention and/or imaging function, microparticle comprises guiding entity (targeting entity).

Summary of the invention

[20] In one embodiment of the present invention, provide microparticle, at least a radiation treatment agent that it comprises core and directly or indirectly is attached to core surfaces.Microparticle can be introduced into by using in the blood vessel, can be used to carry out imaging and/or diagnosis and/or therapeutic and get involved (therapeutic intervention).Therapeutic combination of the present invention comprises radiological predication fallout plot granule (bulk material) suspension in the acceptable liquid on the physiology, and it can be used for being injected in the human body.

[21] use core and connection carrier (linking carrier) (such as, nonrestrictive example, poly-(methyl methacrylate)), it comprises the biocompatibility microsphere, the diameter of microsphere about 5 to about 200 micrometer ranges.Depend on clinical needs, this material can be attached with α, β-or γ-emission radionuclide (emittingradionuclide) or their any combination.

[22] in certain embodiments, the present invention relates to microparticle, this microparticle comprises: core; At least one is positioned at the connection carrier on the described core, and wherein said connection carrier comprises biocompatible polymer; And at least a radiation treatment agent that is covalently bound to described connection carrier; The diameter of wherein said microparticle is about 5 to about 200 micrometer ranges, and described microparticle is non-biodegradability.

[23] in specific embodiments of the present invention, the radiation treatment agent comprises α-emission radionuclide, beta-emitting radionuclide, γ-emission radionuclide or its combination, for example comprise α-emission radionuclide and beta-emitting radionuclide, and/or beta-emitting radionuclide and γ-emission radionuclide, and/or α-emission radionuclide and γ-emission radionuclide.

[24] in some preferred embodiment of the present invention, the radiation treatment agent comprises treats with radionuclide and imaging or diagnosis radionuclide.More specifically, treatment comprises beta-emitting radionuclide with radionuclide, and imaging or diagnosis comprise γ-emission radionuclide with radionuclide.

[25] treatment of considering to be used to microparticle of the present invention includes but not limited to Y-90, Bi-213, At-211, I-123, I-125, I-131, At-211, Cu-67, Sc-47, Ga-67, Rh-105, Pr-142, Nd-147, Pm-151, Sm-153, Ho-166, Gd-159, Tb-161, Eu-152, Er-171, Re-186 and Re-188 with the non-limitative example of radionuclide.Consider to be used for the imaging of microparticle of the present invention or diagnose non-limitative example to include but not limited to Tc-99m, In-111, Ga-67, Rh-105, I-123, Nd-147, Pm-151, Sm-153, Gd-159, Tb-161, Er-171, Re-186, Re-188 and T1-201 with radionuclide.In preferred embodiments, treatment comprises 90Y with radionuclide, and imaging or diagnosis comprise indium-111 or Tc-99m with radionuclide.

[26] in other embodiments, the radiation treatment agent is radionuclide or radiopharmaceutical.Be used for radionuclide of the present invention and include, but are not limited to one or more following substances: iridium, radium, caesium, phosphorus, yttrium, rhenium, actinium, bismuth, astatine, technetium, indium, iodine, and carbon, nitrogen, fluorine, sodium, magnesium, aluminum, silicon, potassium, vanadium, manganese, gallium, niobium, iodine, plumbous, Y-90, Bi-213, At-211, I-123, I-125, I-131, At-211, Cu-67, Sc-47, Ga-67, Rh-105, Pr-142, Nd-147, Pm-151, Sm-153, Ho-166, Gd-159, Tb-161, Eu-152, Er-171, Re-186, Re-188, Tc-99m, In-111, Ga-67, Rh-105, I-123, Nd-147, Pm-151, Sm-153, Gd-159, Tb-161, Er-171, Re-186, Re-188 and T1-201.

[27] radiation treatment agent or be attached on the core directly or indirectly.The example that connection carrier is attached to core indirectly comprises by one or more spacer groups or by the chelating agen group and adhering to.Admissible chelating agen group comprises following at least one: cyclohexyl diethylene-triamine pentaacetic acid part (CHX-DTPA), diethylene-triamine pentaacetic acid (DTPA), ethylenediaminetetraacetic acid (EDTA), 1,4,7,10-tetraazacyclododecanand-N, N ', N, " N " ' tetraacethyl (DOTA), tetraazacyclododecane tetradecane-N, N "; N " N " tetraacethyl (TETA); cyclohexyl 1; 2-ethylenediamine tetraacetic acid (EDTA) (CDTA); ethylene glycol-O, O '-two (2-aminoethyl)-N, N; N '; N '-four-acetic acid (EGTA), N, N-two (acrinyl)-ethylenediamine-N, N '-oxalic acid (HBED), triethylenetetraaminehexaacetic acid (TTHA), hydroxyethyl diamine triacetic acid (HEDTA), HEDP (HEDP), dimercaptosuccinic acid (DMSA), diethylenetriamines tetramethylene see acid (DTTP) and 1-(p-ammonia benzyl)-DTPA, 1,6-diamino hexane N, N, N ', N '-tetraacethyl, DPDP and ethylidene-two (oxygen ethylene itrile group)-tetraacethyl.In preferred embodiments, the chelating agen group comprises DOTA.

[28] example selected that connection carrier is attached to core for example comprises difunctional junctional complex, carbodiimide condensation or disulfide bond.

[29] microparticle of the present invention comprises the core that includes polymer.Polymer can include but not limited to gather (methyl methacrylate); polyacrylate; the ethene-vinyl acetate polymer; the cellulose acetate of acyl substituted; polyurethane; polystyrene; polrvinyl chloride; polyvinyl fluoride; poly-(ethylene imidazoles); chlorosulfonic acid ester polyolefin (chlorosulphonatepolyolefin); polyoxyethylene; their mixture; with their copolymer; poly-phosphazine; poly-(vinyl alcohol); polyamide; Merlon; polyalkylene; polyacrylamide; poly alkylene glycol; polyalkylene oxide; polyalkylene terephthalates; polyvinylether; polyvinyl ester; polyvinyl halides (polyvinyl halide); polyvinylpyrrolidone; poly-Acetic acid, hydroxy-, bimol. cyclic ester; polysiloxanes; their copolymer; alkylcellulose (alkyl cellulose); hydroxy alkyl cellulose (hydroxyalkyl cellulose); cellulose ether; cellulose esters; NC Nitroncellulose or its combination.In all compositionss of the present invention, core is inactive, is attached on the core up to therapeutic agent, just has radioactivity.In specific embodiment, core comprises poly-(methyl methacrylate) and/or polystyrene.

[30] in some embodiments, at least one connection carrier comprises linear polymer, divides branched polymer and/or dendritic.In comprising the specific embodiments of dendritic, dendritic macromole comprises disulfide bond in its core, and/or has exterior layer, has active group on the exterior layer.In preferred specific embodiments, active group is guiding entity (targeting entity) or treatment entity (therapeutic entity).In another preferred specific embodiments, active group comprises amine groups or carboxylic group.

[31] in other specific embodiments, dendritic macromole has at least one terminal functional groups, and this functional group can contact for chelating agen, and described chelating agen can interact with described at least one functional group.This terminal functional groups comprises ester, ether, mercaptan, carbonyl, hydroxyl, amide groups, carboxyl and/or acid imide.

[32] in relating to the specific embodiments of many dendritic macromoles, these dendritic macromoles are monodispersities.

[33] as advantage, microparticle of the present invention can not leach (leach) radionuclide.In certain embodiments, the density of microparticle 1 to 4gm/cm ³In the scope, or more preferably, 1 to 2gm/cm ³In the scope.

[34] in another embodiment, microparticle also comprises second therapeutic agent, and wherein said at least a radiation treatment agent is first therapeutic agent, and described second therapeutic agent is the therapeutic agent different with first therapeutic agent.In specific embodiments, second therapeutic agent comprises at least a following substances: metal-chelating complex, medicine, prodrug, radionuclide, boron additament (boron addend), labelled compound, toxin, cytokine, lymphokine, chemotactic factor, immunomodulator, radiosensitizer, asparaginase, radiohalogen, chemotherapeutic agent and contrast agent.

[35] another microparticle of the present invention comprises core and at least two kinds of radiation treatment agent that are attached to described core.

[36] in specific embodiment, radiation treatment agent of the present invention comprises α-emission radionuclide, beta-emitting radionuclide and/or γ-emission radionuclide.In other specific embodiments, the radiation treatment agent is independently selected from treatment radionuclide and guidance quality radionuclide.In preferred specific embodiments, treatment comprises beta-emitting radionuclide with radionuclide, and the guidance quality radionuclide comprises γ-emission radionuclide.More specifically, beta-emitting radionuclide comprises 90Y, and γ-emission radionuclide comprises indium-111 or Tc-99m.In certain embodiments, the radiation treatment agent is passed through covalent bond separately in conjunction with core.

[37] in one embodiment, microparticle is provided, this microparticle comprises core, at least a radioactivity guiding entity that is attached to described core, wherein said guiding entity comprises γ-emission radionuclide, the diameter of microparticle is about 5 to about 200 microns scope, and right and wrong are biodegradable.In further embodiment, the radiation treatment entity further comprises beta-emitting radionuclide.In another further embodiment, microparticle also comprises at least a connection carrier that is positioned on the described core, and wherein said connection carrier comprises biocompatible polymer.

[38] in another embodiment, the invention provides the granular materials that comprises microparticle, it has: core, at least a connection carrier that is positioned on the described core, wherein said connection carrier comprises biocompatible polymer and at least a radiation treatment agent that is covalently bound to described connection carrier; The diameter of wherein said microparticle is about 5 to about 200 micrometer ranges, and described microparticle right and wrong are biodegradable.In specific embodiment, the diameter of microparticle is in the 8-100 micrometer range, and more specifically, the microparticle diameter is in the 25-50 micrometer range, and most preferably, diameter is in the 20-30 micrometer range.In all examples, the microparticle of granular materials is enough big, to avoid phagocytosis.

[39] the present invention also provides and has used compositions to carry out the method for radiation therapy.

[40] a kind of embodiment of utilizing radiotherapy to treat patient's method comprises, need a plurality of radiological predication fallout plot granules of radiocurable patient, the diameter of each in wherein said a plurality of radiological predication fallout plot granule about 5 to about 200 micrometer ranges, and right and wrong are biodegradable, the radiological predication fallout plot granule comprises core, at least a connection carrier that is positioned on the described core, wherein said connection carrier comprises biocompatible polymer, at least a radiation treatment agent that is covalently bound to described connection carrier, wherein said a plurality of radiological predication fallout plot granules offer patient's radiation therapy.In specific embodiment, a plurality of radiological predication fallout plot granules are by parenteral, intravenous administration, carry out intravascular administration by vascular catheterization, be administered in the arterial vascular system of supporting patient tumors, and/or be administered into the target location such as on the tumor or near.Administering mode can be single dose form and/or inculcate continuously or in a period of time with the multiple dose form administration.In certain embodiments, utilize thromboembolism effect (embolization), a plurality of radiological predication fallout plot granules are fixed on the administration position, such as the target location, such as tumor or be fixed in the arterial vascular system of supporting tumor.

[41] in another embodiment of the present invention, provide the method for blood vessel being carried out the thromboembolism effect, comprised giving a plurality of microparticle of the present invention.In specific embodiment, the thromboembolism effect comprises the suppository compositions is delivered to blood vessel, to be full of or to clog blood vessel and/or the promotion formation of condensing, like this, reduces, reduces or is blocked and/or stop through the blood flow of blood vessel.

[42] method of the present invention can be used for radiotherapy, comprises being used for the treatment of cancer patient and/or tumor, is used for target location to the patient such as tumor imaging, and/or the object that is used for suspection is suffered from cancer or tumor is diagnosed.Method of the present invention is particularly suitable for suffering from the object of following cancer: primary hepatocarcinoma or secondary liver cancer, rheumatoid arthritis, entity tumor, hepatocarcinoma, the brain cancer, breast carcinoma, ovarian cancer, renal cell carcinoma, hepatoma, sarcoma, head or neck cancer or central nerve neuroma.

[43] a kind of method that the intravital Target organ of patient or tumor are carried out imaging comprises, give the patient a plurality of radiological predication fallout plot granules in the intravital target location of patient, the diameter of each in wherein said a plurality of radiological predication fallout plot granule 5 to about 200 micrometer ranges, and right and wrong are biodegradable, the radiological predication fallout plot granule comprises core, at least a connection carrier that is positioned on the described core, wherein said connection carrier comprises biocompatible polymer, at least a radiation treatment agent that is covalently bound to described connection carrier, wherein said radiation treatment agent comprises γ-emission radionuclide; And detecting described a plurality of radiological predication fallout plot granule, wherein said detection provides the image of Target organ or tumor.Detection can be carried out between radiation era, or optionally, carries out after radiation.In further embodiment, this method also comprises the position of the described a plurality of radiological predication fallout plot granules of detection in the patient.Can consider a plurality of microparticles are fixed on the target location, the target location comprises Target organ or tumor.

[44] in certain embodiments, method of the present invention relates to the diagnosis of interior cancer of patient's body and/or tumor.This kind method comprises many radiological predication fallout plot granules of the present invention is imposed on the patient, preferably imposes on the position that target location such as suspection is tumor, or the position of preinvasive cancer or Secondary cases cancer; Detect described many radiological predication fallout plot granules and determine by testing result whether the patient suffers from cancer and/or tumor, wherein detect described tumor and/or cancer and show it is positive diagnosis.This kind diagnostic method can consider to be used for diagnosing liver cancer, entity tumor, the brain cancer, breast carcinoma, ovarian cancer, renal cell carcinoma, hepatoma, sarcoma, central nerve neuroma, and/or head and/or neck cancer.

[45] in other embodiments, the test kit that is used to prepare granular materials of the present invention is provided, this test kit comprises: the on-radiation core, at least aly be used for that at least a radionuclide is attached to the connection carrier of described granular core and be used to prepare the guidance (instructions) of described microparticulate therapeutic agents amount (microparticle treatment dose) or be used to obtain the instrument of such guidance.In specific embodiments, test kit also comprises radionuclide, and it can provide respectively with test kit.In a specific embodiments, test kit also comprises and is selected from following at least a component: pharmaceutically acceptable inert carrier, preparaton (formulating agent), adjuvant, active agent, water, saline, transfer ligand (transfer ligand), Reducing agent, lyophilization aid, stabilization aid, solubilizing agent, antibacterial, cushion, x-ray contrast agent, acoustic contrast agent and metal medicine.In another kind of specific embodiments, test kit also comprises and is selected from following at least a component: syringe, shielding device and imaging device.In the further specific embodiments of another kind, test kit also comprises at least two kinds of chemically different on-radiation cores, or at least two kinds of chemically different connection carrier.

[46] in another embodiment, provide the method for using test kit of the present invention.A kind of method of using test kit described herein is to prepare the microparticulate therapeutic agents amount for the patient who needs the microparticle treatment, comprise: determine type and the dosage that required microparticle is treated, the described microparticulate therapeutic agents amount of the tool manufacture of utilizing described guidance maybe can obtain to instruct by described patient's prescription.

[47] the another kind of method of using test kit of the present invention to come to prepare the microparticulate therapeutic agents amount for the patient who needs the microparticle treatment comprises: type and the dosage of being determined needed microparticle treatment by described patient's prescription, select the type of on-radiation core in the core from described test kit, select the type of junctional complex in the junctional complex from described test kit, the selective emission nucleic, the described microparticulate therapeutic agents amount of tool manufacture that maybe can obtain to instruct by described guidance.

[48] another aspect of the present invention relates to the method for thromboembolism, comprises the suppository compositions is delivered to blood vessel, and to be full of or to clog blood vessel and/or the promotion formation of condensing, the blood flow by blood vessel reduces or stops like this.The suppository compositions comprises granular materials of the present invention and pharmaceutically acceptable carrier.

The accompanying drawing summary

[49] Fig. 1: the exemplary of microsphere structure, this microsphere structure is made of the biocompatible core that the mode by chemistry is connected to chelating agen, and chelating agen is binding radioactivity emitter (emitter) tightly.Radiosiotope can be subjected to the support at dendritic macromole interface, to increase the quantity of bonded chelating agen.

[50] Fig. 2 .PMMA-PAMAM dendritic macromole conjugate is synthetic.

[51] Fig. 3 .PMMA-DOTA microsphere is synthetic.

[52] Fig. 4. microparticle.

Detailed Description Of The Invention

I. definition

[53] in order to make following description clear, provide following definitions.

[54] " microparticle (microparticles) " or " microsphere (microspheres) " refers to support its lip-deep effect The particle of thing material. The microparticle right and wrong are biodegradable, and are biocompatibilities.

[55] " abiotic degradable (non-biodegradable) " refers to such material, its can be during not treating quilt Health is degraded to serious degree.

[56] " biocompatibility (biocompatible) " refers to the health nonhazardous, and be pharmaceutically acceptable, non-carcinogenic The property, and can seriously not cause the bodily tissue inflammation.

[57] as used herein, " connection carrier (linking carrier) " is for the effector molecules molecule is attached to The molecule of microparticle. This attachment can form covalent bond with effector molecules and microparticle matrix.

[58] " effector molecules (effectoe) " is the molecular structure that can comprise chelating agent, and it brings into play useful biology in vivo Function. As used in this article, the term treatment is used to refer to any chemical combination with effector molecules (therapeutic effector) Thing or molecule or isotope, it causes in destination organization, initiation or active cell is replied or physiologic response.

[59] " chelating agent (chelator) " or " bonding unit (bonding unit) " refer on reagent binding molecule such as The part of metal ion (moiety) or group, this combination are by forming with one or more donor atoms Chemical bond is realized.

[60] as used herein, " health (body) " preferably refers to human body, but should be appreciated that health is also passable Refer to non-human animal's body.

II. the present invention

[61] the present invention relates to treatment radioactivity composition and application thereof, the present invention has overcome externally radiotherapy Three main limitation of the non-specific radiation of observing in (extenal radiation therapies): 1) make Make normal peripheral liver cell exempt from injury with the β radiation as therapeutic agent; 2) be directly delivered to tumor vascular system, The radiological predication fallout plot particle will rest in the tumour then, so that normal cell and/or tissue around the tumour exempt from injury; With 3) so that enough can transmit the dose of radiation that quantity increases greatly, own thereby obtain will effectively eliminate basically The radiation scope of entity tumor (for example radiation of the upper effective dose for the treatment of).

[62] the present invention relates to by the radioactivity that forms with the radioisotope labeling biocompatible polymer compound Thing; Microsphere/the granular core of the polymer of support formation microparticle-radioactivity compound; With for the preparation of radiation " kit " of the necessary component of property compound. In addition, the present invention relates in vivo spoke of its preparation method and its Penetrate the methods and applications of diagnosticum and/or therapeutic agent aspect.

Microparticle

Treatment group compound of the present invention relates to microparticle. In certain embodiments, microparticle of the present invention comprises Core, at least one is positioned at the connection carrier on the described core, and wherein said connection carrier comprises biocompatibility Polymer, at least a radiation treatment agent that is covalently bound to described connection carrier; Wherein said microparticle Diameter is about 5 to about 200 micrometer ranges, and described microparticle right and wrong are biodegradable.

[63] microsphere is made of non-pottery, nonradioactive labeling's core material, and it serves as the support of polymer coating Thing, polymer coating by linear, branch or dendritic biocompatible polymer consist of suitable knot Close reagent and be attached to polymer coating. Described binding reagents is optional from a large amount of chemically stable compounds, this A little compound binding radioactivities or on-radiation therapeutic agent are referring to more detailed description herein.

[64] in the present invention, at polymer (the locally deposited of the lip-deep local deposits of microsphere core Polymer), be used as carrying out to radionuclide or being fixed of radiopharmaceutical and to it that locality transmits Carrier.

[65] can use for local radiation treatment (local radiotherapy) (brachytherapy (brachytherapy)) standard radionuclide is such as rhenium, iodine, iridium, radium, caesium, yttrium or other elements Radionuclide.

[66] suitable therapeutic agent and diagnosticum comprise those materials, and its efficient in vivo is based on them and is retained in blood The ability that is delivered in the tube chamber crack or in lacuna vasorum is predicted. Therefore, relate to and give the present composition Method can easily apply to treat some diseases and obstacle, comprise cancer and/or tumour; And/or apply to By various imaging techniques imaging is carried out in the selected zone of mammal; And/or suspection had cancer and/or swollen Knurl suspects that particularly the object that has cancer and/or tumour in the liver diagnoses.

[67] in specific embodiment, by attaching to linear, branch or dendritic macromole polymer bag Chelating agent on the clothing, microparticle or microsphere comprise any or all following substances: phosphorus, yttrium, rhenium and/or its He β launches isotope; Actinium, bismuth, astatine and other α emission isotope; Technetium, indium, iodine and/or other γ emission Isotope; With carbon, nitrogen, fluorine, sodium, magnesium, aluminium, silicon, potassium, vanadium, manganese, gallium, niobium, iodine and/or lead. [68] can select microsphere, with degraded or the extinction of acquisition greater than 320 hours longer time, and At this moment, 5 of the Yttrium-90 of implantation half-life have finished and most radioactive decay takes place.

[69] the invention utilization of describing herein has the technology and equipment in the hospital of examining medical ability. The present invention also relates to And " kit ", kit comprises polymer spheres, attachment and radio isotope, its can mix at the scene or Mix in local radiopharmaceutical chamber. This advantage has increased flexibility, so that can be according to preplanned dosimetry Determine that dosage is to satisfy the needs of single patient. The invention provides and carry the single of γ and β or alpha ray source Or a plurality of trace labellings. Characteristics of the present invention are to solve two kinds of knotty problems with existing microsphere, that is, Can not imaging and locate subsequently the problem of the limited distribution of the problem of microsphere and product.

[70] the invention provides the microparticle structure, comprising: biocompatibility microparticle core, optional connection is carried Body and directly be coupled to or indirectly be coupled to the molecular effect thing of biocompatible core. The preferred shape of effector molecules Formula is radio isotope, and it is attached to connection carrier by the chelating agent group. In addition, the present invention includes " reagent Box " preparation method and their internal radiation diagnosticum and/or the therapeutic agent purposes of preparation.

[71] in certain embodiments, the diameter of biocompatibility microsphere is in 10 to 200 microns scope.

[72] in certain embodiments, biocompatible core comprises material non-pottery, the nonradioactive labeling, It serves as the holder (referring to Fig. 1) of the polymer coating on core surfaces, and polymer coating is by line style, branch Or dendroid biocompatible polymer formation, be attached with suitable binding reagents on it. Binding reagents is selected from each Plant chemically stable compound, these compound binding radioactivities or on-radiation therapeutic agent. Biocompatibility Polymer can be attached with α, β-and/or γ-emission radionuclide, or its any combination, and this depends on and faces Bed needs.

[73] problem that spills from the ceramic microspheres filter in order to overcome radionuclide is simultaneously in order to keep the microsphere tool Low-density is arranged, the invention provides the microsphere with improved physical property. Microparticle (microballoon of the present invention Body) can be mixed with such size, shape and density, namely wait the object machine of being treated when they are applied to When official's artery was supplied with, they had the distribution character of improvement. In addition, compared with the prior art microsphere, every One microsphere can transmit the ionising radiation of higher quantity. This so mean, transmit same dose of radiation, Need relative lesser number (still less product) to give to target organ. In selectable embodiment, microballoon Body is being made laggard row labels, thereby improves manufacturing technology level.

[74] the chemical durability of microsphere is such, and when being applied, they can not put a large amount of radiation-emittings Injectivity isotope (radiation emitting radioisotope) is discharged in the circulatory system.

The microparticle core

[75] extensible material of the present invention (augmentation material) comprises smooth disc, spherical basically The particulate substrates material, preferred biocompatible polymer. Term " basically spherical (substantially spherical) " Refer to such fact, some in the particle of the present invention can be spheroids, and most of particle of the present invention is in shape Be to look like spheroid, just they are spherical. Term used herein " (rounded) of disc " or " light (smooth, the rounded) of cunning, disc " refer to such practical work, even particle of the present invention is not accurate sphere, They can not have any edge sharp or that the angle is arranged (angular edges) yet. Particle must be enough big To avoid phagocytosis.

[76] as used herein, term " microparticle (microparticles) " exponential quantity median diameter (number Median diameter) is particle greater than 5 microns. In specific embodiment, microparticle is the quantity meta The number diameter is greater than about 10 microns particle. For example, core diameter can be about 10 microns to about 200 microns. Also Preferably, the diameter of microparticle about 20 to about 80 micrometer ranges.

[77] yet, should be appreciated that for injection, the upper limit of particle size will be established by employed specific injection The standby decision. That is to say that particle must be enough little, to avoid when being injected, assembling and blocking syringe. Annotate The typical range of penetrating usefulness preferably is being no more than about 35 microns narrow and small particle about 10 in about 150 microns In the size range, more preferably be no more than about 20 to about 30 microns scope, most preferably having basic The upper particle size that equates.

[78] the microparticle diameter can about 10 microns to about 200 micrometer ranges.In one embodiment, the diameter of microparticle about 8 to about 100 microns scope.In another embodiment, the diameter of microparticle about 20 to about 30 micrometer ranges.

[79] these are exemplary, are not restrictive.Also can use overall size range other narrow and small particle size range in 10 to 150 micrometer ranges.When these scopes of discussion, should be appreciated that in the practice, a spot of granule outside ideal range may reside in the extensible material sample of the present invention.Yet in any given sample, most granule should be in the scope of expectation.Preferably, 90% granule is in the scope of expectation, and most preferably, the granule of 95-99% is in the scope of expectation.

[80] as used herein, term " particle size (particle size) " exponential quantity median diameter, this is to measure with the conventional granulates size measurement technique that those of ordinary skills know, for example laser diffractometry, photon correlation spectrum (photon correlation spectroscopy), precipitation field flow fractionation (FFF) (sedimentationfield flow fractionation), rotating disc type centrifuging (disk centrifugation) or electrical sensing zone method (electrical sensing zone method).Preferred laser diffractometry.Term " quantity median diameter (numbermedian diameter) " is as the function reflection distribution of particles (quantifying) of particle diameter.Another alternative representation of the particle size that often use this area is " volume median diameter (volume mediandiameter) ".Volume median diameter is the median diameter of volume weighting distribution of sizes (volume weighted size distribution).Volume median diameter has reflected volume distributed median as the function of particle diameter.

[81] in preferred embodiments, the diameter of microparticle is selected according to the size of the desired region of its health that is deposited in.Residing in the organ of health or the purposes of the microparticle in the zone is common (Flaimet al, J Pharmacol.Meth.11:1-39,1984 in blood flow research; Heymann et al, Prog.Cardiovasc.Dis.20:55-79,1977).For example, select to reside in microparticle diameter in the capillary tube usually between 15 to 35 microns.Use various method well known by persons skilled in the art, microparticle can be got by different polymer manufacture.The numerous methods that are used to prepare the microparticle of any particle size range are known.The synthetic method of material preparation microparticle by fusing is known, is included in emulsion, in spray droplets (sprayed drop) with in that independently the stage is carried out polymerization.For solid material or preforming glue, known method comprises wet grinding or dry grinding, micronization, utilizes air nozzle (airjet) or sieve to carry out classification and similar approach.

[82] the granular materials of the present invention density that to also have a preferred feature be microparticle 1 to 4gm/cm ³In the scope, more preferably 1 to 2gm/cm ³In the scope.

[83] in the present invention, the local deposits polymer is stored on the surface of microparticle core, as immobilization and localized delivery radionuclide or radiopharmaceutic carrier.

[84] in one embodiment, microparticle is water inexpansibility (not water swellable).

[85] the radiation treatment agent is not preferably contained in the inside of described core.Selectively, microparticle of the present invention comprises γ-emission radionuclide, and it directly or indirectly is attached to core.In specific embodiment, consider γ-emission radionuclide to be carried out adhewsive action by being molded into to come in the spheroid, for example, during its preparation, adhere to, preferably attached to the surface.In specific embodiment, the surface is the resin particle surface, many resin particles and γ-emission radionuclide and core are mixed, molding, such as high temperature and/or high pressure, act on core surfaces by described molding and form resin-radionuclide layer, thereby obtain the radiological predication fallout plot granule.

Biocompatibility microparticle core material

[86] the preferred microparticle core of the present invention polymer that is biocompatibility.Suitable biocompatible polymer or can be slowly biodegradable maybe can be non-Biodegradable polymeric, maybe can be their mixture or copolymer, describes referring to this paper.Being suitable for biocompatible polymer of the present invention therefore can be that water-insoluble or minimum degree is water miscible.

[87] if any catabolite of polymer and polymer is nontoxic to the receiver, and to receiver's health do not have significantly harmful or adverse influence such as immunne response at injection position, polymer is a biocompatibility so.

[88] suitable biocompatibility, abiotic degradable polymer comprises and is selected from following abiotic degradable polymer: the polymer of the cellulose acetate of polyacrylate, ethene-vinyl acetate and other acyl substituted (acylsubstituted cellulose acetates), non-degradability polyurethane, polystyrene, polrvinyl chloride, polyvinyl fluoride, poly-(ethylene imidazoles), chlorosulfonic acid ester polyolefin, polyoxyethylene, their mixture and their copolymer.

[89] representational synthetic polymer comprises poly-phosphazine, poly-(vinyl alcohol), polyamide, Merlon, polyalkylene, polyacrylamide, poly alkylene glycol, polyalkylene oxide, polyalkylene terephthalates, polyvinylether, polyvinyl ester, polyvinyl halides, polyvinylpyrrolidone, poly-Acetic acid, hydroxy-, bimol. cyclic ester, polysiloxanes, polyurethane and its copolymer.The natural polymer of synthetic modification comprises alkylcellulose, hydroxy alkyl cellulose, cellulose ether, cellulose esters and NC Nitroncellulose.Other interested polymer include, but are not limited to: methylcellulose, ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl emthylcellulose, hydroxy butyl methyl cellulose, cellulose acetate, cellulose propionate, acetylbutyrylcellulose, cellulose acetate-phthalate, carboxymethyl cellulose, cellulose triacetate, sodium sulfate salt cellulose (cellulose sulfate sodium salt), poly-(methyl methacrylate), poly-(ethyl methacrylate), poly-(butyl methacrylate), poly-(isobutyl methacrylate), poly-(N-Hexyl methacrylate), poly-(isodecyl methacrylate), poly-(lauryl methacrylate), polymethylacrylic acid phenylester (poly (phenyl methacrylate)), poly-(acrylic acid methyl ester .), poly-(isopropyl acrylate), poly-(Isobutyl 2-propenoate), poly-(acrylic acid stearyl), polyethylene, polypropylene, Polyethylene Glycol, polyoxyethylene, polyethylene terephthalate, polyvinyl acetate, polrvinyl chloride, polystyrene, polyvinylpyrrolidone and polyvinylphenol.

[90] these polymer can be from Sigma Chemical Co., St.Louis, Mo., Polysciences, Warrenton, Pa., Aldrich, Milwaukee, Wis., Fluka, Ronkonkoma, N.Y., and BioRad, Richmond, Calif. obtains, and can be synthesized into by the monomer that obtains from these suppliers by using standard technique.

[91] the suitable polymers compositions preferably has inherent and controllable biodegradability, and like this, they are adhered to about 1 thoughtful about 6 months; And be nontoxic, do not contain the big monomer of toxicity and be degraded into avirulent component; It is biocompatibility; With wait that the material that is transmitted is that chemistry is compatible, by adhering to (adherence) or geometrical factor (geometric factors), such as being hunted down by the position in expectation, can remain on the position of using; Can be by having minimum invasive technology (techniques of minimum invasivity) such as being transmitted by intubate.

[92] be used for acceptable molecular weights for polymers of the present invention and can be determined that by considering various factors the factor of consideration is such as depolymerization speed, physical characteristic such as mechanical strength, the dissolution velocity of polymer in solvent of expectation by those of ordinary skills.Usually, the acceptable molecular weights scope about 2,000 dalton to about 2,000,000 dalton.(polymer molecular weight is represented with weight average molecular weight usually.Yet for dendritic macromole, when they had definite chemical constitution, the molecular weight of report was absolute molecular weight.)

[93] in one embodiment, the biocompatible polymer of biocompatible polymer core and described connection carrier comprises different biocompatible polymers.

Connection carrier

[94] preferred connection carrier is the macromole aggregation (such as polymeric dendritic macromole) of biocompatible polymer (such as HPMA), biocompatibility component, or many-component connection carrier, it constitutes (such as the polymer micropellet of dendritic macromole bag quilt) by more than one biocompatibility component.

[95] example of connection carrier includes but not limited to: polymerization copolymer, dendritic macromole, Polyethylene Glycol make up, add medicated cap polylysine (capped polylysines), poly hydroxybutyric acid, glucosan, biocompatible polymer and copolymer, such as hyaluronic acid and acrylamide and derivant thereof, granules of polystyrene and its derivant.Preferred connection carrier is a dendritic macromole.

[96] according to the concrete chemical characteristic that relates to, connection carrier can be coupled to effector by the whole bag of tricks.Coupling will be a covalency.Being suitable for that guiding entity and treatment are coupled to the whole bag of tricks of connection carrier with effector can be referring to Hermanson, " Bioconjugate Techniques ", Academic Press:New York, 1996; With " Chemistry of Protein Conjugation and Cross-linking ", S.S.Wong, CRC Press, 1993.Concrete coupling method includes, but are not limited to: use difunctional junctional complex, carbodiimide condensation, disulfide bond formation and use specific combination to (binding pair), wherein in conjunction with one of them right composition on connection carrier, and in conjunction with another right composition on effector.A large amount of effectors can be attached on the microparticle.

[97] water-soluble polymer (dendritic macromole, PEG etc.) can be elected to be the biocompatibility junctional complex, to avoid that immunne response takes place when the administration.

The dendritic macromole connection carrier

[98] another preferred connection carrier is a dendritic macromole.Dendritic macromole is to have from prostheses, clear and definite ramose polymer (for example " star-type polymer (starburst polymers) ").With the polymer phase ratio of routine, it is hyperbranched macromole that dendritic macromole trends towards.Dendritic macromole is described in United States Patent (USP) 4,507,466,4,558,120,4,568,737,4,587,329,4,631,337,4,694,064,4,737,550 and 4,857,599 and a large amount of other patents and patent disclosure in.The structure of dendritic macromole, synthetic and characteristic determine are set forth in the following document: Kim and Zimmerman, " Applications of dendrimers inbio-organic chemistry, " Current Opinion In Chemical Biology (1998) 2 (6): 733-42; Tamand Spetzler, " Chemoselective approaches to the preparation of peptide dendrimers andbranched artificial proteins using unprotected peptides as building blocks; " BiomedicalPeptides, Proteins ﹠amp; Nucleic Acids (1995) 1 (3): 123-32; Frechet, " Functional polymersand dendrimers:reactivity, molecular architecture, and interfacial energy, " Science (1994) 263 (5154): 1710-5; Liu and Frechet, " Designing dendrimers for drug delivery, " Pharmaceutical Science and Technology Today (1999) 2 (10): 393401; Verprek andJezek " Peptide and glycopeptide dendrimers.Part I, " Journal of Peptide Science (1999) 5 (1): 5-23; Veprek and Jezek, " Peptide and glycopeptide dendrimers.Part II, " JournalOf Peptide Science (1999) 5 (5) 203-20; Tomalia et al., " Starburst dendrimers:Molecular-level control of size; shape; surface chemistry; topology, and flexibility fromatoms to macroscopic matter " Angewandte Chemie--International Edition in English (1990) 29 (2): 138-175; Bosman et al., " " Chemical Reviews (1999) 99 (7): 1665-1688 for About dendrimers:Structure, physicalproperties, and applications; Fischer andVogtle, " Dendrimers:From design to application--A progress report, " AngewandteChemie-Intemational Edition (1999) 38 (7): 885905; Roovers and Comanita, " Dendrimers And dendrimer-Polymer Hybrids, " Advances In Polymer Science (1999) 142:179-228; Smith and Diederich, " Functional dendrimers:Unique BiologicalMimics, " Chemistry--A European Journal (1998) 4 (8): 1353-1361; With Matthews et al., " Dendrimers--Branching out from curiosities into new technologies, " Progress InPolymer Science (1998) 23 (1): 1-56.The synthetic synthesis cycle that uses usually repeatedly of dendritic macromole, this makes and can control size, shape, surface chemistry, elasticity and the inner topology structure of dendritic macromole.The example that is suitable as the dendritic macromole that connects entity is described in Wu et al., " Metal-Chelate-dendrimer-Antibody Constructs for Use in Radioimmunotherapy andImaging, " Bioorganic and Medicinal Chemistry Letters (1994) 4 (3): among the 449-454.

[99] by utilizing various chemical bond technology to come in conjunction with guiding entity and treatment entity, dendritic macromole can be used as connection carrier easily.For example at United States Patent (USP) 6,020, in 457, disclose and in its core, have two sulfur (--the S--S--) dendritic macromole of key, dendritic macromole can make up by the method for describing in this United States Patent (USP) and get.The final skin of dendritic macromole can add medicated cap (end-blocking) with active group such as amine groups or carboxylic group.These active groups then or can or can carry out derivatization treatment with treating entity (or use in some cases both mixture) with the guiding entity.

[100] dendritic macromole that is used for the object of the invention is ramose polymer, it is the three-dimensional chemical compound of going up high-sequential, the response hierarchy of wherein ramose oligomerization/poly sequence by repeatedly be formed at core molecule (nuclearmolecule) around, it has the outer surface of positively charged under certain conditions, and this is suitable (polycation dendritic macromole) that functional end group caused.This class dendritic macromole and their preparation method are described in WO 84/02705, United States Patent (USP) 4,507,466,4,558,120,4,568,737,4,587,329,4,631,337,4,694,064,4,713,975,4,737,550,4,871,779,4,857,599, among EP 0234408, EP 0247629, the EP 0271180, and particularly be described in Tange et al., supra, WO 95/02397 and Tomalia etal. are among the supra.

[101] being suitable for dendritic macromole of the present invention comprises, for example, daiamid (polyamidoamine) is dendritic macromole (PAMAM), it can be by progressively adding two kinds of monomers: methacrylate (ester) and ethylenediamine, round as ammonia, three-(2-amino-ethyl) amine (TAEA) of core element or ethylenediamine (EDA) synthetic (Tanget al., supra).The preferred primary amine group of the end group of this type of dendritic macromole.Preferred the 5th, the 6th, the 7th generation PAMAM dendritic macromole, particularly the 6th generation PAMAM dendritic macromole are referring to Tang et al., supra..The theoretical molecular of this type of PAMAM dendritic macromole, the quantity of terminal amine and hydrodynamic radius can be referring to Tang et al., the disclosures of supra.Table 1 has shown the characteristic of amine functions PAMAM dendritic macromole.

Table 1.

[102] dendritic that can be used generally comprises any known dendritic structure, comprises dendritic macromole, regular dendron (dendron), controlled oversubscription branched polymer (controlled hyperbranchedpolymer), tree-shaped branch grafting (dendrigrafts) and oversubscription branched polymer at random.Dendritic is the polymer with intensive branched structure, has a large amount of active groups.Dendritic comprises the recurring unit in several layers or some generations, and it all contains one or more branch points.The condensation reaction preparation that dendritic---comprises dendritic macromole and oversubscription branched polymer---by the monomer unit with at least two active groups gets.Operable dendritic macromole comprises those by the dendritic macromole that many dendrons constitute, and described many dendrons distribute (emanate) by common core and come out, and this core can be single atom or one group of atom.Each dendron generally includes the end surface group, has the inside branch binding site (interior branch iunctures) and the covalently bound bivalence junctional complex (connectors) near branch abutment of the subfunction group (branching functionalities) more than or equal to two.

The oversubscription branched polymer that [103] can be used has been represented a class dendritic, and compared with the almost completely dendron and the dendritic macromole of regular texture, it contains high-caliber nonideal irregular branch.Particularly, the oversubscription branched polymer contains the big relatively irregular stub area of quantity, wherein, is not that branch's binding site is all contained in each recurring unit.Dendritic macromole, dendron, the preparation and the sign of oversubscription branched polymer, controlled oversubscription branched polymer and tree-shaped branch grafting are known at random.Dendritic macromole and dendron, the example that synthesizes their method is described in United States Patent (USP) 4,410,688,4,507,466; 4,558,120; 4,568,737; 4,587,329; 4,631,337; 4,694,064; 4,713,975; 4,737,550; 4,871,779 and 4,857,599.Oversubscription branched polymer and their example of method of preparation for example are described in United States Patent (USP) 5,418, in 301.

[104] be suitable for dendritic of the present invention and also comprise macromole, be often referred to cascade molecule (cascademolecule), arborols, tree-shaped scion grafting molecule (arborescent grafted molecules) and analog.Suitable dendritic also comprises bridge-type dendritic (bridged dendritic polymer), promptly, dendritic macromole that perhaps links together or couple together by the link molecule that surface functional group is linked together and the dendritic aggregation that combines by physical force by surface functional group.Also comprise spherical dendritic and rod dendritic, they are grown by polymer core.

[105] United States Patent (USP) 5,338, and 532 have instructed the polymer conjugates that comprises dense star-type polymer (dense star polymers), and dense star-type polymer and carrier material interrelate, and the disclosure of this patent is incorporated herein by reference.(one type dense star-type polymer is Starburst ^TMPolymer (trade mark of The Dow ChemicalCompany), wherein dendritic macromole is daiamid (PAMAM)).The various suitable applications of this type of conjugate are discussed in United States Patent (USP) 5,338, and in 532, this patent comprises the transmission carrier of these conjugates as bioactive agents.United States Patent (USP) 5,338,532 have exemplified the application of zero-valent state metal and ionic metal or radioactive metal, and Fe, Rh, Pd, Y, Fn, Pb, Gd, Mn and Gd have especially given an example.

[106] be suitable for dendritic of the present invention and also comprise macromole, be often referred to cascade molecule (E.Buhleier et al. for example, Synthesis 155-158 (Feb.1978); Arborols (for example United States Patent (USP) 5,376,690 and 5,210,309); Tree-shaped scion grafting molecule; Tectodendrimer (Srinivas Uppuluri et al. for example, " Tecto (endrimer) Core-shell Molecules:Macromolecular Tectonics for the SystematicSynthesis of Larger Controlled Structure Molecules " PMSE, Spring Meeting (Mar.21-25,1999) 55-56) and analog.Suitable dendritic also comprises the bridge-type dendritic, promptly, perhaps dendritic macromole that links together by surface functional group or by the link molecule that function of surface is specifically linked together and the dendritic aggregation that is fixed together by physical force.Also comprise spherical dendritic (for example United States Patent (USP) 4,507,466; 4,588,120; 4,568,737; 4,631,337; 4,587,329 and 4,737,550, their disclosure is by with reference to being incorporated herein) and rod dendritic (for example United States Patent (USP) 4,694,064, their disclosure by with reference to being incorporated herein), it is grown and gets from polymer core.Be applicable to that other dendritics of the present invention comprise all basic dendritic structures, wherein specific chelation group or part are arranged in the prostheses of dendritic macromole, and/or be positioned at the internal structure of dendron arm, and/or be positioned on the surface of dendritic macromole.Will be understood that all above-mentioned these dendritic macromole terms all are included in the term " dendritic (dendritic polymer) ".

[107] dendritic that is used for practice of the present invention comprises those having the dendritic of symmetric part of matrix unit (symmetricalbranch cells) (brachium equates, for example the PAMAM dendritic macromole; For example be described in United States Patent (USP) 5,527, those in 524) and those have the dendritic of asymmetric subdivision, and (brachium is unequal, for example lysine-branch's dendritic macromole for example is described in United States Patent (USP) 4,410, in 688 those), branch's dendritic macromole, cascade molecule (E.Buhleier et al. for example, Synthesis 155-158 (Feb.1978)), arborols (for example United States Patent (USP) 5,376, and 690 and 5,210,309) and analog.

[108] dendritic that is used for practice of the present invention can be to go up (generationally polydisperse) monodispersity (generationallymonodisperse) or that go up polydispersity from generation to generation from generation to generation.Dendritic in monodispersity solution is basically with generation, and so size and dimension unanimity.Dendritic in polydispersity solution comprise be distributed with different from polymer.The dendritic polymer molecule that can be used for practice of the present invention comprised by different inside and outside compositions or mixture that functional group is formed.The example of suitable dendritic comprises poly-(ether) dendron, dendritic macromole and oversubscription branched polymer, poly-(ester) dendron, dendritic macromole and oversubscription branched polymer, poly-(thioether) dendron, dendritic macromole and oversubscription branched polymer, poly-(aminoacid) dendron, dendritic macromole and oversubscription branched polymer, poly-(aryl alkylene ether (arylalkyleneether)) dendritic and poly-propylamine dendritic macromole, dendritic macromole and oversubscription branched polymer.(PAMAM) dendritic macromole is particularly useful in preparation metallic complex of the present invention to have been found that poly-(amide amine).

[109] being considered in practice of the present invention the most useful dendritic is approximate monodispersity.That is to say, the preferred dendritic in monodispersity solution, all dendritic polymer molecules are the same generation basically in monodispersity solution, and are consistent on size and dimension therefore.The monodispersity solution of preferred especially dendritic macromole.

[110] dendritic that is preferred for practice of the present invention has terminal functional groups, and it can contact for the chemical compound that contains chelating agen, and it can interact with functional group.

[111] term " functional group (functional group) " is intended to comprise such group such as ester group, ether group, thiol group, carbonyl group, oh group, amide group, carboxylic group and imide group and their combination.With amine is that terminal daiamid, polymine and polypropylene imines dendritic macromole also is known, for example from United States Patent (USP) 5,393,797; 5,393,795; 5,560,929; With 5,387,617, all these patents all belong to Hedstrand etc.

[112] can mix threaded tree dendritic macromolecules (linking dendrimers) arbitrarily, to increase the polyvalency of yttrium attachment site.The a plurality of sites that can adhere to the yttrium chelating agen can be contained on the microsphere surface.Yet because the surface of microsphere can be inflexible, chemical modification is the reaction of difficulty.Therefore, may need junctional complex to increase and spherome surface between distance, react with chelating agen helping.If what obtain at spherome surface is the suboptimum concentration of chelating agen, then can adhere to junctional complex.

The size of dendritic macromole

[113] common, by the step-reaction of multifunctional monomer or reaction repeatedly, obtain branched structure, thereby prepare dendritic macromole.For example, at United States Patent (USP) 5,530, in 092, (primary diamine) is initial with primary diamine, and acrylonitrile is carried out two Michael addition reactions (double Michael addition) repeatedly, carry out hydrogenation reaction then, each initial amine obtains two primary amines.This makes the number of primary amine group double.Therefore, with two amine-initiated, in shell, first generation dendritic macromole (G1) has 4 primary amines; The second filial generation (G2) has 8 primary amines; The third generation (G3) has 16 primary amines; In the 4th generation (G4), have 32 primary amines; In the 5th generation (G5), have 64 primary amines, by that analogy.These polyamine dendritic macromoles we can say that for the Degradation in the hydrolysis be stable.

[114] can be used for the algebraically of the dendritic of practice of the present invention, and the variation of the size of dendritic can be quite big.For example, poly-(amide amine) dendritic macromole (3.5PAMAM) in 3.5 generations can be used for practice of the present invention.Yet the dendritic of higher or lower algebraically also can be expected to be used for the present invention, but have ethylenediamine (EDA) core, the PAMAM dendritic macromole of algebraically in 3.5 to 7.5 scopes be useful especially.

Be coupled to the method for connection carrier

[115] this method is intended to effector is covalently attached to connection carrier.Utilize the surface of connection carrier and the junctional complex part between the effector, this covalent attachment effect can directly be carried out between connection carrier surface and effector.Some operable junctional complexs are described in United States Patent (USP) 5,527,524; EP 0353450; EP 0570575; In EP 0296522, the disclosure of these patents is incorporated this paper into by reference.

[116] usually, at connection carrier and effector, and can be randomly, and form between the spacer groups connect before, one of them chemical functional group will be activated.Persons of ordinary skill in the art will recognize that and use various standard methods and condition, various chemical functional groups comprise that hydroxyl, amino and carboxyl can be activated.

[117] typically, use the chemical technology of standard, by they chemical functional groups separately, reagent is covalently bound on connection carrier.Can be randomly, connection carrier or reagent are coupled to reagent by one or more spacer groups.When being used in combination, spacer groups can be identical or different.Similarly, if more than one connection carrier is used to produce reagent-connection carrier complex, dendritic macromole can be identical or different.

[118] in certain embodiments, during a step or multistep reaction of the conjugate of assembling connection carrier or connection carrier, one or more active groups are protected.Those skilled in the art will know that how to protect specific functional group, so that it does not react with a selected group reaction condition.The example of useful blocking group, for example referring to Greene et al., Protective Groups in Organic Synthesis, John Wiley ﹠amp; Sons, NewYork, 1991.

[119] any method in many methods of knowing by those of ordinary skills, the effector molecule can be attached to connection carrier.Usually, effector or directly or by dendritic macromole or other junctional complexs (sept) be attached on the microparticle.

[120] selectively, microparticle and/or sept can carry out derivatization, to expose or to adhere to extra activity functional groups.Derivatization can relate to any junctional complex molecule that adheres in many junctional complex molecules, such as those from Pierce Chemical Company, the junctional complex molecule of Rockford Ill.

[121] have two with the specific effect thing on the difunctional junctional complex of the functional group that reacts of group can be used for forming the conjugate of expectation.

[122] many methods and the junctional complex molecule that is used for all cpds is attached to protein such as antibody is known (for example referring to european patent application 188,256; United States Patent (USP) 4,671,958,4,659,839,4,414,148,4,699,784,4,680,338,4,569,789 and 4,589,071; With Borlinghaus et al. (1987) Cancer Res.47:4071-4075), described all cpds comprises the radionuclide metal chelating agen, toxin and medicine.

Spacer groups (Spacer Groups)

[123] between connection carrier and therapeutic agent, can at random introduce one or more spacer groups.Spacer groups contains at least two chemical functional groups.Typically, a chemical functional group of spacer groups is attached on the chemical functional group of connection carrier, and another chemical functional group of spacer groups is used to be attached to the chemical functional group of therapeutic agent.The example of the chemical functional group of spacer groups comprises hydroxyl, sulfydryl, carbonyl, carboxyl, amino, ketone and mercapto groups.Spacer groups also can be united use.When uniting the use spacer groups, spacer groups can be identical or different.Spacer groups is optional part, and it can be introduced into to increase the length of junctional complex, and like this, it further comes with the microsphere spaced surface, thereby produces motility, and helps to react with the chelating agen of radionuclide (that is yttrium).

[124] no matter be direct coupling or by the sept coupling, reagent preferably is coupled to connection carrier by covalent bond.Covalent bond can be a non reversibility, and part is reversible, or completely reversibility.Reversible degree is corresponding to the sensitivity (susceptibility) of vivo degradation with reagent-connection carrier complex (agent-linking carrier complex).It will be apparent for a person skilled in the art that the reversible group of this kind can be incorporated into any position of connection carrier-agent combinations.The spacerarm (spacer arm) that introducing has reversible connection is an exemplary embodiment; Key between reagent and the dendritic macromole for example also can be reversible.

[125] reagent-connection carrier complex can be that unconjugated medicament is confirmed by research complex hydrolysis or enzymatic conversion method to the sensitivity of degraded.In a word, use this method, find good dependency between external and the activity in vivo.Referring to Phipps et al J.Pharm.Sciences 78:365 (1989).For example, can easily determine conversion ratio by spectrophotometric method or by solution-air or high pressure lipuid chromatography (HPLC).Then, use standard technique, half-life and other kinetic parameters can calculate.Referring to Lowry et al.MECHANISMANDTHEORY IN ORGANIC CHEMISTRY, 2nd Ed., Harper ﹠amp; Row, Publishers, New York (1981).

Effector

[126] connection carrier can be connected to and be used for the treatment of or identify on the various effectors of diseased tissue.Preferably, the effector that is coupled to polymer conjugate (polymer conjugate) is selected from therapeutic agent or diagnostic agent.

[127] example that is used for therapeutic agent of the present invention includes, but are not limited to metal-chelating complex, medicine, prodrug, radionuclide, boron additament, labelled compound, toxin and other effector molecules, such as cytokine, lymphokine, chemotactic factor, immunomodulator, radiosensitizer, asparaginase, boron additament and radiohalogen.Preferably, the therapeutic agent that can be incorporated on the polymer body frame is selected from treatment radiosiotope, toxin, medicine, prodrug and boron additament.

[128] be used for medicine of the present invention and include but not limited to any present approval or also unratified chemotherapeutic agent, go up just passable as long as it can be attached to polymer conjugates (polymer conjugate).The typical available medicine of having ratified includes but not limited to the derivant of following reagent and these reagent: Anastrozole (anastrozole), azacytidine, bleomycin A5,1,4-dimethane sulfonoxybutane, carboplatin, carmustinum, chlorambucil, cisplatin, cladribine, cyclophosphamide, cytosine arabinoside, dacarbazine, actinomycin D, daunorubicin, Docetaxel (docetaxel), amycin, estramustine, etoposide, fluorine urine deoxynucleoside, the arabinose fluoroadenine, fluorouracil, flutamide, gemcitabine, hydroxyurea, the hydrochloric acid Carubicin, ifosfamide, irinotecan, chlorethyl cyclohexyl nitrosourea, chlormethine, megestrol, melphalan, purinethol, ammonia first dish purine, mitomycin, mitotane, mitoxantrone, paclitaxel (paclitaxel), pentostatin, the methylbenzyl hydrazine, tamoxifen, teniposide, thioguanine, tespamin, hydroxy-camptothecin seals, vinblastine, vincristine and vinorelbine.

[129] in addition, polymer conjugates can comprise therapeutic agent, and therapeutic agent is made up of the boron additament that (BNCT) uses in the scheme at boron neutron capture therapy (BoronNeutron Capture Therapy).BNCT is a binary system, and design is used for ionizing radiation is delivered to tumor cell, and the neutron irradiation of this boron by tumor-localizing-10 atoms is carried out.BNCT is based on nuclear reaction, and when stable isotope, i.e. nuclear reaction takes place when producing α granule and Li-7 nucleon with the thermal neutron irradiation B-10 of isotope enrichment (natural abundance with 19.8% exists).It is so long that these particulate footpaths are about the diameter of a cell, thereby produce high linear energy transfer (linear energy transfer).The short distance 1.7MeV α granule that only needs minority to produce in this nuclear reaction just is enough to targeted cells nuclear and destroys nucleus.Cancer is successfully carried out BNCT, the boron-10 of high concentration need be positioned at the method for knub position, meanwhile make the essentially no boron of non-target organs.Compositions and method that the msAb of targeting in advance (pre-targeting msAb) that use is used for BNCT treats patient tumors are described in United States Patent (USP) 6,228, in 362, and can easily make amendment according to the present invention, and this patent is by with reference to incorporating this paper into.In addition, other elements also are applicable to neutron-capture reaction (neutron capture reactions).An example is a uranium.A large amount of uranium can be by the chelating agen of natural generation such as the ferritin combination.This kind strategy has been described in the prior art, for example is described in United States Patent (USP) 6,228,362 and the document quoted of this patent in, and easily revise and be used for the present invention, so these documents are incorporated this paper into by reference in its entirety.

[130] diagnostic agent is the embodiment of the present invention of contrast agent, by illustrating with reference to the contrast agent (metal chelate-based contrast agents) based on metal-chelator.To the concentrated description of metal-chelator is exemplary rather than restrictive.Those skilled in the art will recognize that except metal-chelator, many contrast agent can be coupled to (for example granule, iodinated aryl compounds (iodinated arylcompounds), nitroxide etc.) on the connection carrier of the present invention.

[131] in preferred embodiments, treatment interrelates by chelating agen and microparticle structure with metal ion.

[132] a large amount of metal-chelators are known in the art.For example referring to Pitt et al., " The Design ofCheating Agents for the Treatment of Iron Overload, " In, INORGANIC CHEMISTRYIN BIOLOGY AND MEDICINE; Martell, Ed.; American Chemical Society, Washington, D.C., 1980, pp.279-312; Lindoy, THE CHEMISTRY OFMACROCYCLIC LIGAND COMPLEXES; Cambridge University Press, Cambridge, 1989; Dugas, BIOORGANIC CHEMISTRY; Springer-Verlag, New York, 1989 and be included in wherein list of references.

[133] in preferred embodiments, diagnostic reagent is the metal composite of polyaminocarboxylate chelating agen (polyaminocarboxylatechelating agent), polyaminocarboxylate chelating agen such as diethylene-triamine pentaacetic acid (DTPA).

[134] in other preferred embodiments, the treatment entity is chemotherapeutant or prodrug or toxin, wherein treats the surface that entity is attached to connection carrier.Selectively, the treatment entity is hunted down (entrapped) or is encapsulated in the connection carrier.

[135] in particularly preferred embodiments, treatment combines with chelating agen with radionuclide, and this chelating agen is attached on the polymer surfaces of microparticle structure by the method for chemistry.In another particularly preferred embodiment, 90Y is that to use radionuclide, DOTA be chelating agen in treatment.

Chelation group (Chelating groups)

[136] chelation group is well known to those skilled in the art.Wu et al. (1992) Nucl.Med.Biol., 19 (2): 239-244 discloses the synthetic of macrocyclic chelants, is used for using ¹¹¹In and ⁹⁰Y carries out radioactive label to protein.

[137] the preferred water-soluble chelator that is used for practice of the present invention includes but not limited to: diethylene-triamine pentaacetic acid (DTPA), ethylenediaminetetraacetic acid (EDTA), 1,4,7,10-tetraazacyclododecanand-N, N ', N, " N " ' tetracetate (DOTA), tetraazacyclododecane tetradecane-N, N ", N " N "-tetraacethyl (TETA); cyclohexyl 1; 2-ethylenediamine tetraacetic acid (EDTA) (CDTA); ethylene glycol-O; O '-two (2-aminoethyl)-N, N, N '; N '-tetraacethyl (EGTA), N, N-two (acrinyl)-ethylenediamine-N, N '-oxalic acid (HBED), triethylenetetraaminehexaacetic acid (TTHA), hydroxyl ethylenediamine triacetic acid (HEDTA), the hydroxyl ethylene acid esters (HEDP) of seeing, dimercaptosuccinic acid (DMSA), diethylenetriamines tetramethylene see acid (DTTP) and 1-(p-ammonia benzyl)-DTPA, 1-N, N, N ', N '-tetraacethyl, DPDP, ethylene (oxygen ethylene itrile group)-tetraacethyl and cyclohexyl diethylene-triamine pentaacetic acid part (CHX-DTPA).

[138] a kind of chelating agen, 1,4,7,10-tetraazacyclododecanand-N, N, N ", N " '-tetraacethyl (DOTA) is meaningful especially, this be because it can the many diagnosis of chelating on and treatment go up important metal, such as radionuclide and radioactive label.

[139] in some embodiments of the present invention, DOTA or other chelating agen conjugates such as EDTA or DTPA, for example can get with the form preparation of water soluble salt (sodium salt, potassium salt, 4-butyl ammonium, calcium salt, iron salt etc.).These salt can be as the therapeutic agent of oncotherapy.The second, DTPA or other chelating agen also can be used as diagnostic agent, when its with radionuclide such as ¹¹¹In or ^99mDuring the Tc labelling, can be used as radioactive indicator, be used from nuclear imaging technology (nuclear imaging techniques) and detect some tumor.

[140] in some embodiments, chelating agen contains 1,4,7,10-tetraazacyclododecanand-N, N ', N ", N " '-tetraacethyl (DOTA), perhaps chelating agen is 1,4,7,10-tetraazacyclododecanand-N, N ', the derivant or the chelating agen well known to those skilled in the art of N ", N " '-tetraacethyl (DOTA).In other embodiments, chelating agen comprises ionizable group such as carboxyl, phosphate, phosphonate, sulfate, sulfonate or sulfinate.In other embodiments, chelating agen comprises single ionizable group, and described single ionizable group produces such surface, this surface can in conjunction with have+2 or bigger, or+3 or the isotope and the metal of bigger valence state.

[141] can make amendment and change the structure of water-soluble polymer of the present invention or water-soluble metal chelating agen, the molecule that acquisition still has similar or other ideal characterisiticses is also included among the present invention such as " biological function equivalent (biologicallyfunctional equivalents) " or " function equivalent (functional equivalents) ".

[142] characteristic of medical applications makes the chemical property of potential cheland (chelating ligand) need satisfy multiple requirement.It must be strong (multiple tooth (multidentate)) complexant of (a) metal ion; (b) hydrophilic, in water, to have dissolubility; (c) nontoxic; (d) can be incorporated in the protein structure, and can not cause protein denaturation.For each single radionuclide, the technical staff must design special chelating system in fact.For example, macro ring bifunctional chelating agent, particularly DOTA, the derivant of mixing 90Y and indium-Ill has demonstrated excellent dynamic stability under physiological condition.Yet yttrium-DOTA complex forms slowly, and this has proposed individual technical barrier, and promptly this can cause radioactive label to yield poorly, unless controlled condition carefully.

[143] the most successful chelating agen of preparation radioactivity conjugate (radioconjugates) is compound organic synthetic product.The quite representational example of synthetic method can be referring to Brechbiel, M.W.; Gansow, O.A.; Atcher, R.W.; Schlom, J.; Esteban, J.; Simpson, D.E.; Colcher, D., Synthesis of 1-(P-isothiocyanatobenzyl) Derivatives of DTPA and EDTA.Antibody Labeling andTumor Imaging Studies, Inorg.Chem., 1986,25,2772-2781.Be preferred for other chelating agen of the present invention and comprise this class chelating agen of heterocycle chelating agen.

[144] as used herein, term " heterocycle (heterocycle) " or " heterocyclic system (heterocyclicsystem) " are meant stable 5,6, or 7-unit's monocycle or dicyclo or 7,8,9, or 10-unit bicyclic heterocycle, it is saturated, (fragrance) fractional saturation or undersaturated, it is made up of carbon atom and 1,2,3 or 4 hetero atom, and hetero atom is selected from N, NH, O and S independently of one another, and comprising any bicyclic radicals, wherein any above-mentioned heterocycle can be fused on the phenyl ring.Nitrogen and sulfur heteroatom can randomly carry out oxidation.

Radionuclide

[145] by attaching to the chelating agen of connection carrier, microparticle of the present invention can contain any or all following element: phosphorus, yttrium, rhenium and other β emission isotope; Actinium, bismuth, astatine and and other α emission isotopes; Technetium, indium, iodine and other γ emission isotope; With carbon, nitrogen, fluorine, sodium, magnesium, aluminum, silicon, potassium, vanadium, manganese, gallium, niobium, iodine and/or lead.

[146] as used herein, treatment is such nucleic with radionuclide, the conversion (nuclear decay) that its experience is spontaneous, and energy shifts to be enough to the radiant energy of cytotoxicity quantity is imposed on peripheral cell.In comparison, diagnostic radionuclide institute radiation emitted can be with the horizontal penetrate tissue of the cell injury of minimum.By using suitable scintillography thing (scintigraphic imager), can detect this kind radiation.Treatment of the present invention includes, but are not limited to Y-90, Bi-213, At-211, I-123, I-125, I-131, At-211, Cu-67, Sc-47, Ga-67, Rh-105, Pr-142, Nd-147, Pm-151, Sm-153, Ho-166, Gd-159, Tb-161, Eu-152, Er-171, Re-186 and Re-188 with radionuclide.Diagnosis nucleic of the present invention or imaging nucleic include but not limited to Tc-99m, In-111, Ga-67, Rh-105, I-123, Nd-147, Pm-151, Sm-153, Gd-159, Tb-161, Er-171, Re-186, Re-188 and T1-201.

[147] any useful nucleic can use within the scope of the present invention.Particularly preferably be such radionuclide, it has useful diagnosis or treatment characteristic, respectively such as indium-111 or 90Y.

What [148] further consider is, in the embodiment of using more than one radionuclide, these a plurality of radionuclides can be dissimilar (alpha emitter, beta emitter and/or gamma emitters), and can be alpha emitter, beta emitter and/or the gamma emitter of different subgroups.

[149] the β radioactive exposure that produces from 90-yttrium inside sources (internal sources) is in tumor tissues and normal hepatocyte, and this is because radiation scope surpasses 1cm.α-irradiation is attracting potential treatment isotope, can unite use with the 90-yttrium, or alternative 90-yttrium, provides the radiation scope (micron order) of much shorter in tissue, and for the distance of same weak point, has high relatively radiation activity again.The present invention also comprises the alpha emitter radionuclide is coupled to the microsphere granule, separately and γ-and/or β-emitting isotope coupling, or with other α granule couplings.The radiological predication fallout plot granule can carry out administration by inculcating into Hepatic artery, and is trapped in the liver tumor capillary bed (liver tumor capillary bed), thereby can transmit high-intensity radiation of killing tumor dose, and can not be exposed to normal hepatic tissue.Being contemplated that this kind therapeutic agent can be used for radiation therapy, with the treatment liver tumor, is fatal if these liver tumors are not treated without exception.

[150] combining closely of radioactive metal nucleic needs the chelating agen of radioactive metal.Be used for low-molecular-weight chelating agen is carried out radiolabeled standard Radiolabelling method and preventive measure also can be used to prepare radiolabeled chelating agen polymer.For example, use the method for radioactive metal such as indium-1ll and 90Y, generally need highly purified radionuclide to supply with, the various buffer solution of deionized water preparation, and during the radioactive label program, employed glass drying oven and plastic ware are carried out pickling with reagent.

[151] use the program of radioactive metal such as rhenium-188 to need the electronation step to finish labelling, this method is preferably used the buffer (oxygen-depleted buffers) that exhausts oxygen and is used argon atmospher to cover the reaction of (overlay) radioactive label when implementing.The coordination sphere of radionuclide (coordination sphere) comprises all parts or the group that is incorporated into this radionuclide.For transition metal radionuclide M _t, in order can to stablize, it has usually by more than or equal to 4 and be less than or equal to the ligancy (number of donor atom) that 9 integer constitutes; That is to say have 4 to 9 atoms to be attached to metal, can be described as and have complete coordination sphere.The needed definite ligancy of stable radionuclide complexes is determined by the type of the characteristic of radionuclide, its state of oxidation and donor atom.

Test kit

[152] the present invention also comprises test kit." test kit " comprises various components, and this is referred to as preparation, and they are in one or more phials, and it is used by the final enforcement user in clinical or pharmacy environments, with the composite diagnosis radiopharmaceutical.

[153] when radioactive effect thing or other effectors during as diagnostic agent and/or therapeutic agent, if the expectation user can use ready-to-use (ready-for-use) compositions, this usually is impossible.This is because the shelf life of radiolabeled chemical compound is short and/or the half-life of employed radionuclide is short.In such cases, user can carry out the labeled reactant of radionuclide in clinical hospital, doctor's purser's room or laboratory.In order to reach this purpose or other purposes, various reactive components then can offer user with the form of so-called " test kit ".The reaction necessary operations that the test kit that decision design is such, these test kits can make implementation period hope is simple as much as possible, thereby makes user to prepare compositions desired from test kit by the facility that uses him to have.Therefore, the present invention also relates to be used to prepare the test kit of compositions of the present invention.

[154] this kind test kit of the present invention preferably includes microparticle of the present invention.The microparticle structure can be provided, if desired, add pharmaceutically acceptable inert carrier and/or preparaton and/or adjuvant.In addition, test kit can randomly comprise the solution of the chelating agen (or other chemical reagent) of salt or suitable radionuclide, and description, and description and prescription one are used to be used and/or react the component in the test kit.

[155] test kit provides and has been used for synthetic and all essential components of use diagnostic radiopharmaceutical, except those for the common component of final enforcement user, such as the solution of the water of injection or saline, radionuclide, during synthesis of radiopharmaceuticals, be used to heat the equipment of test kit, if necessary, radiopharmaceutical is offerd medicine to the necessary equipment of patient, such as syringe and shielding device (shielding equipment) and imaging device.

[156] test kit can contain transfer ligand (transfer ligand), Reducing agent, lyophilization aid, stabilization aid, solubilizing agent and antibacterial and active microparticle and bonded effector.

[157] " transfer ligand " is such part, and complex in the middle of itself and metal ion form, this centre complex enough are stablized preventing undesired side reaction, but also enough instability to be converted into metal medicine (metallopharmaceutical).Middle being formed on the kinetics of complex is favourable, and being formed on the thermokinetics of metal medicine is favourable.The transfer ligand that is used to prepare the metal medicine and be used for diagnostic kit---it is used for preparation diagnosis radiopharmaceutical---includes but not limited to gluconate, gluceptate, mannitol, glucarate, N, N, N ', N '-ethylenediaminetetraacetic acid, pyrophosphate and methylene diphosphonate.In a word, transfer ligand is made up of oxygen or nitrogen donor atom.

[158] " Reducing agent (reducing agent) " is such chemical compound, itself and radionuclide---it is normally obtained as the chemical compound of relative non-activity, high oxidation state---reaction, to reduce its state of oxidation by transferring an electron on the radionuclide, thereby make it have more activity.The Reducing agent that is used for radiopharmaceutical preparation and diagnostic kit---it is used to prepare radiopharmaceutical---includes but not limited to stannum dichloride (stannous chloride), tin bifluoride (stannous fluoride), formamidine sulfinic acid, ascorbic acid, cysteine, hydrogen phosphide and cuprous salt or iron salt.Other Reducing agents are described in Brodack et.al.; In the PCT application 94/22496, they incorporate this paper into by reference.

[159] " lyophilization aid (lyophilization aid) " is the component that has favourable physical characteristic such as the vitrification point of lyophilization, and lyophilization aid is added in the preparation, is used for the physical characteristic of all components of freeze dried preparation with improvement.

[160] lyophilization aid of---it is used to prepare radiopharmaceutical---includes but not limited to mannitol, lactose, sorbitol, glucosan, ficoll (Ficoll) and polyvinylpyrrolidone (PVP) to be used to prepare diagnostic kit.

[161] " stabilization aid (stabilization aid) " is so a kind of component, and it is added in radiopharmaceutical or the diagnostic kit, so that stablize radiopharmaceutical, perhaps prolongs the service life of test kit before it must be used.Stabilization aid can be antioxidant, Reducing agent or free radical scavenger (radical scavenger), and can improve stability with other components of degraded or radiopharmaceutic substance reaction by preferential.

[162] be used for radiopharmaceutic preparation and at diagnostic kit---it is used to prepare radiopharmaceutical---useful stabilization aid includes but not limited to ascorbic acid, cysteine, thioglycerol (monothioglycerol), sodium sulfite, sodium pyrosulfite, gentisic acid and inositol.

[163] " solubilizing agent (solubilization aid) " is such component, and it improves the dissolubility of one or more other components in the required medium of preparation.

[164] be used for radiopharmaceutic preparation and be used for diagnostic kit the solubilizing agent of---it is used to prepare radiopharmaceutical---includes but not limited to ethanol, glycerol, Polyethylene Glycol, propylene glycol, polyoxyethylene sorbitan monoleate, dehydrated sorbitol mono-fatty acid ester, polysorbate, poly-(oxygen ethylene) block copolymer (Pluronics) of poly-(oxygen ethylene) poly-(oxypropylene) and lecithin.Preferred solubilizing agent is Polyethylene Glycol and Pluronics.

[165] buffer that is used for radiopharmaceutical preparation and is used for diagnostic kit---it is used to prepare described radiopharmaceutical---includes but not limited to phosphate, citrate, sulfosalicylate and acetate.More complete enumerating can be referring to United States Pharmacopeia.

[166] antibacterial that is used for radiopharmaceutical preparation and is used for diagnostic kit---it is used to prepare radiopharmaceutical---includes but not limited to benzylalcohol, benzalkonium chloride, chlorobutanol and methyl hydroxybenzoate, nipasol or butoben.

[167] diagnosis also can have more than one function with the component in the test kit.Reducing agent also can serve as stabilization aid, and buffer can serve as transfer ligand, and lyophilization aid also can serve as transfer, assists or be total to-part (co-ligand), and is like that.

[168] treatment offers terminal user with radiopharmaceutical, x-ray contrast agent medicine, ultrasonic contrast agent medicine and the metal medicine that is used as magnetic resonance imaging contrast with the final form of preparation, and described preparation is included in the bottle with lyophilized solid or with the form of aqueous solution usually.End user's water or saline reconstruct freeze dried substance take out patient dose, or only are that patient dose (patient dose) is provided from the aqueous solution preparation that provides.

[169] by in aqueous solution, in 0 to 100 ℃ temperature, mix salt, chemical compound of the present invention and the Reducing agent of radionuclide, make technetium of the present invention and rhenium radiopharmaceutical easily.Technetium and rhenium radionuclide be the form of pertechnetate or perrhenate preferably, and is pharmaceutically acceptable cation.The preferred sodium pertechnetate of pertechnetate form is such as the sodium pertechnetate from the Tc-99m manufacturer of commerce.The quantity that is used to prepare the radiopharmaceutic pertechnetate of the present invention can be in 0.1mCi to 1Ci scope, more preferably in 1 to 200mCi scope.

[170] being used to prepare the quantity of technetium of the present invention and the radiopharmaceutic The compounds of this invention of rhenium can be in 0.01 μ g to 10mg scope, more preferably in 0.5 μ g to 200 μ g scope.The amount of using depends on the quantity of other reactants and the radiopharmaceutic characteristic of the present invention to be produced.

[171] by in aqueous solution, in 0 to 100 ℃ temperature, mix the salt and the reagent of the present invention of radionuclide, be easy to prepare the radiopharmaceutical of indium of the present invention, copper, gallium, silver, palladium, rhodium, gold, platinum, bismuth, yttrium and lanthanide series.These radionuclides normally obtain as the form of the dilute aqueous solution in all example hydrochloric acids of mineral acid, nitric acid or sulphuric acid.With radionuclide and to about 1,000 normal reagent mix of the present invention that are dissolved in the aqueous solution.Buffer is generally used for the pH of reactant mixture is maintained between 3 to 10.

[172] Zhi Bei total time can change, and this depends on the characteristic of metal ion, the characteristic and the quantity of reactant, and preparation method.Preparation can be completely, produces＞80% radiopharmaceutical product in 1 minute, or needs more time.If desired or want to obtain more highly purified metal medicine, product can carry out purification with any technology in many technology well known to those skilled in the art, such as liquid chromatography (LC), Solid-Phase Extraction, solvent extraction, dialysis or ultrafiltration.

[173] when the test kit composition is used as the component that pharmaceutically is applied (for example as injecting fluid), they should be aseptic.When composition provided with the state of doing, user preferably used aseptic normal saline solution as solvent.If desired, composition can be stable with conventional method with suitable stabilizers, suitable stabilizers such as ascorbic acid, gentisic acid or these sour salt, or they can comprise other auxiliary reagents, for example implant such as glucose, lactose, mannitol and analog.

[174] be supplied to the test kit of user also can comprise component defined above, and operation instructions, yet the solution of the salt of top definition radionuclide or chelating agen has limited shelf life, and they can offer user independently and handle.

[175] test kit can randomly comprise compositions operation instruction and/or prescription extraly, and they are used to instruct the reaction between the component of test kit, to form the product of expectation.When existing, although guiding material material normally hand-written or that print, they are not limited thereto.Can preserve this kind guidance and they are transferred to any instrument of terminal user all within consideration of the present invention.This kind instrument includes but not limited to electron storage medium (for example disk, tape, cartridge, chip), optical medium (for example CD ROM) and analog.This type of medium can comprise IP address, and this Internet provides this kind guiding material.

Pharmaceutical composition

[176] can use liquid carrier transfer microparticle, the liquid carrier can be any biocompatible materials that microparticle can be delivered to the desirable tissue position, such as biocompatibility suspension, solution or other forms of fluid.

[177] pharmaceutical composition of the present invention is specially adapted to parenteral, such as intravenous administration.The compositions that is used for using will comprise the microparticle solution that is dissolved in the preferred aqueous carrier of pharmaceutically acceptable carrier usually.Can use various aqueous carriers, such as buffer saline and analog.These solution are aseptic, do not have unwanted material usually.These compositionss can be sterilized with conventional known sterilization technology.If desired near physiological condition, compositions can contain pharmaceutically acceptable auxiliary substance, such as pH regulator agent and buffering reagent, toxicity regulator and analog, for example sodium acetate, sodium chloride, potassium chloride, calcium chloride, sodium lactate and analog.

[178] compositions of the present invention also can comprise other components, such as pharmaceutically acceptable excipient, adjuvant and/or carrier.For example, compositions of the present invention can be prepared with excipient.The example of this type of excipient comprises water, saline, Ringer's mixture, dextrose solution, mannitol, Hank ' s solution and other moisture physiological equilibrium's saline solution (aqueous physiologically balanced salt solutions).Excipient also can contain minor amounts of additives, such as the material that increases isotonicity and chemical stability.The preparation that contains the Aquo-composition of active component is known in the art.Usually, this type of preparation of compositions becomes injectable forms, is liquid solution or suspension; Also can be prepared into and be suitable for before injection, making compositions solution or suspension, solid form.

[179] " pharmaceutically acceptable (pharmaceutically acceptable) " is meant those chemical compounds, material, compositions and/or dosage form, it is in reliable medical judgment scope, be applicable to the tissue of humans and animals body and contact, and can not cause too much toxicity, stimulation, anaphylaxis or other problems or complication, have rational benefit/risk than balanced.

[180] diagnosis, is diagnosed with radiopharmaceutical normally in saline solution by the intravenous injection administration with radiopharmaceutical, and dosage is 1 to 100mCi, or preferred 5 to 50mCi.Use known method to carry out imaging.

[181] treatment with radiopharmaceutical by the intravenous injection administration, normally in saline solution, dosage be every 70kg body weight for humans 0.1 to 700mCi, or the dosage of preferred 0.5 to 10mCi/kg body weight.

[182] for the parenteral in aqueous solution, for example, if necessary, solution should carry out suitable cushioning effect, and liquid diluent is at first handled with imbibitions such as enough saline or glucose carry out.According to the situation of the object of just being treated, be necessary on dosage, to do some variations.Under any circumstance, the personnel that are responsible for administration will determine proper dosage for each is individual.Also have, for human administration, preparation should satisfy FDA Office ofBiologics standards desired aseptic, do not have heat and general safety and a purity rubric.

[183] sterile injectable solution gets by following method preparation, reactive compound is incorporated in the suitable solvent with required quantity, if desired, some kinds that reactive compound can be in above-named other components are mixed, and then carry out filtration sterilization.Usually, be incorporated into by the active component with the various bacterium of going out and prepare dispersion in the sterile carrier, sterile carrier contains basic dispersion medium and above-mentioned needed other components.

[184] practical methods of the compositions of preparation parenteral is known or conspicuous to those skilled in the art, and be described in more detail in the open source literature such as Remington ' s Phamaceutical Science, 15thed., Mack Publishing Company, Easton is among the Pa. (1980).

[185] for injection, reagent of the present invention can be prepared in aqueous solution, preferably on physiology in the compatible buffer such as preparing in Hanks ' s solution, Ringer's mixture or the normal saline buffer solution.

[186] and dosage and the frequency that can stand needed according to the patient can give compositions by single or multiple.Under any circumstance, compositions should provide the microparticle of the present invention of sufficient amount to treat the patient effectively.The therapeutic agent of effective quantity can be any amount or the dosage that is enough to bring advantageous effects in the treatment, and this part ground depends on situation, type and the position of cancer, patient's size and situation, and other factors that those skilled in the art will know that.Dosage can be used as single dose and gives, or multiple dose gives, for example, and gradation administration in the time in some weeks.

The patient selects and estimates

[187] in certain embodiments of the invention, microparticle of the present invention is used for radiation therapy.What can imagine is, those of ordinary skills know such method, by this method screening and/or determine the patient, to treat with the radiation therapy method, more specifically, treats with radiological predication fallout plot granule of the present invention.In non-limitative example, the patient that need carry out radiation therapy comprises the patient of a line of accepting standard and second line treatment (standard first and second line therapies) and failure.The expert of suitable medical science subject such as medical science oncology, radiation oncology and interventional radiology (interventional radiology) can be before the contact treatment scheme, the evaluation and test patient.Patient's selection is based on satisfying some parameter, and such as the age, (confirmed diagnosis of a non-hematologic malignancy) diagnosed in the affirmation of non-blood foul disease, and the unresectable disease that can measure is such as liver tumor.Ideally, the patient can provide and inform back letter of consent (informed consent), and ECOG behavior score value (ECOG Performance Status) is less than or equal to 2.In certain embodiments, need radiocurable patient to have enough bone marrow (granulocyte＞1500/ μ l, platelet＞60,000/ μ l); Competent liver function (bilirubin≤2.0mg/dl, SGOT/SGPT, or 5 times of alkali phosphatase＜normal level upper limit) and enough pulmonary function (FEV ₁＞1L).Known to art technology, the patient does not avoid angiography and selectivity internal organs catheterization (selective visceral catheterization), or＞10% pulmonary shunt or any flow (any flow to the GI tract) that flows to intestines and stomach.Some can not carry out the radiocurable patient of the present invention is the pregnant woman, the patient who suffers from liver blood stream (hepatofugal blood flow), air cock phlebothrombosis (complete portal veinthrombosis), or before to estimate absorbed dose＞30Gy, accepted patient, or in the treatment time in 4 weeks, need the chemotherapeutical patient who carries out system also to be not suitable for this treatment from pulmonary's irradiation in any source.

[188] before the final decision of making about the microsphere radiation therapy, carry out comprehensive medical history and health detection (treatment group is the joint study group that radiation tumor worker, medical science tumor worker and intervention radiation worker form) by treatment group.Suitable blood work (blood work) comprises liver functional test, electrolyte (electrolytes), whole blood counting (complete blood count), with diversity, PT, PTT, INR, lipase and suitable tumor marker are studied its grade malignancy (CEA, AFP, CA 19-9, Chromogranin A, CA27-29,5-HIAA etc.).All these laboratory parameters can inculcate the back a period of time in the compartment of terrain carry out repeatedly with the monitoring toxicity, preferably after inculcating, carry out once weekly, carried out for 8 weeks, and then biweekly and/or every month subsequently once.

[189] carry out in the radiocurable embodiment relating to the patient who diagnosis is had hepatocarcinoma, whatsoever tumor type is all estimated the patient by breast, abdomen and pelvis ct scanning, makes great efforts to detect other hepatic metastases (hepaticmetastasis).Hepatocyte cancer patient also uses liver contrast agent (contrast of the liver) to carry out MRI usually, to determine knub position, size and quantity better.For further assistance tumor load with to replying for the treatment of, the patient who has neuroendocrine tumor accepts In- ¹¹¹Octreoscan (OctreoScanTM Kit, Indium In- ¹¹¹Pentetreotide, Mallinckrodt Medical Inc., St.Louis, MO, USA).Every other non-liver cancer patient accepts FDG-PET scanning, and this is before the treatment and the routine examination after the treatment.Based on the three-dimensionalreconstruction of liver,, carry out the contrast-agent-free CT scan of liver in radiation oncology (Radiation Oncology department) at preplanned dosage.Then volume data is used to calculate the definite activity of microparticle for single patient.Distribute with MAA-SPECT scanning estimation microsphere, based on microsphere distribution calculated dose distribution, the calculating of dose distribution is assisted by these plan CT scan (planning CT scans) of record.

[190] utilize femoral catheter method (femoral catheter approach), abdominal part, aorta and liver blood vessel are drawn.Treatment group checks only pipeline, and determines the liver capacity (hepatic volumes) by right and/or left Hepatic artery supply, plan and Rapid Dose Calculation before this helps to treat.Usually, in angiography at least one when week before treatment, implement; Sometimes, before transmitting the microsphere treatment, reality implements during maximum 3 weeks.If determine that during angiography gastroduodenal artery microsphere probably takes place escapes into intestines and stomach, so just carry out embolic coil art (coil embolization).In both cases, tumor has parasitic tremulous pulse (parasitized arteries) near barrier film, and it is lived so that microsphere is minimized along membranous deposition by thromboembolism.

(Shunt Evaluation) estimated in shunting

[191] pass through 4.5-6.0-mCi ^99mThe MAA macro aggregated albumin of Tc-labelling (macro aggregated albumin) (MAA) carries out plane and SPECT imaging, and all patients are tested by the latent shunting (occult shunt) of Hepatic artery system to lung or the intestines and stomach Venous system.The particulate size of MAA is similar to the size of microsphere, but the MAA granule carries out imaging and quantitative by gammacamera easily.Each ^99mTc-MAA inculcates and contains 1,000,000 microparticles of 3.6-6.5 usually, and＞85% microparticle is (Package insert ofPulmolite between 20 μ tm and 40 μ tm

-CIS-US, Inc, 10DeAngelo Drive, Bedford, Massachusetts, USA).All patients are carried out plane and SPECT imaging, to determine whether to exist distributary phenomenon better.Be limited to 30Gy or 16.5mCi on the accumulative total accumulated dose of giving lung that this scheme proposes.In some cases, if in lung, the Tc99m MAA activity of inculcating is checked through 10% absolute minute flow valuve in screening study (screening study), if perhaps in intestines and stomach, detect anatomical shunting (anatomic shunting), the patient is deprived the qualification of radiation therapy so, to prevent lung toxicity.Because diverting coefficient estimates that (shunt fraction estimate) is subjected to the influence of employed estimation routine deeply, we select the geometric average analytical method that free liver region of interest (liberal hepatic region of interest) (ROI) is analyzed.By increasing image intensity to include from most of scatterings of that organ, liver ROI gains freedom.At background (background), revise all ROI counting, background below liver and then abdomen area and avoid urethra.More preceding and after the whole body plane picture in (whole body planar images), draw region of interest round liver and lung, use following formula to calculate the branch flow valuve:

Diverting coefficient=ROI lung counting/(ROI lung counting+ROI liver counting)

[192] carry out the SPECT imaging better determining whether to exist the intestines and stomach shunting, and provide before three-dimensional data and the treatment and mutual relation is set up in the PET scanning after the treatment.

[193] in inculcating 24 hours of microsphere, all patients get back to the nuclear medicine chamber, obtain plane and torso SPECT image, and these images are produced by discharging bremstrahlen (γ) radiation by microsphere itself.This quality assurance test (quality assurance test) proves that radiation dose only is deposited on (just on the target location) in the liver, and can with pretreatment ^99mThe activity distribution of seeing in the Tc-MAA scanning is compared.

Radiotherapy treatment planning

[194] in typical patient evaluation, the patient accepts the CT treatment plan in radiation oncology (Radiation Oncology department), use v.4.0 software (Picker International of AcQ-sim, Inc., 595Miner Rd.Highland Hts., OH 44143), from the liver profile reconstruct liver volume of describing by the radiation oncologist (livervolumes) (whole liver, lobus dexter and lobus sinister).Under the situation that does not have IV contrast agent or oral contrast material (oral contrast), use the thick thin slice of 3mm to carry out CT scan, the patient holds the breath during the liver imaging.The patient's who records based on the nominal target dosage (nominal target dose) of 150Gy with by the AcQ-sim data liver quality, calculate the needed activity of each patient, suppose microparticle uniform distribution (Package Insert, TheraSphere in whole liver volume

, MDS Nordion, Inc., 447March Road, Ontario, CanadaK2K 1X8):

A(GBq)＝D(Gy)×M(kg)/50

Wherein A is active, and D is a nominal target dosage, and M is the liver quality.For the liver quality is the typical patient of 2Kg, and needed activity is 6GBq.With the lung dose maintenance below 30Gy preventing radiation pneumonia, thereby with the patient of patient's selectional restriction at diverting coefficient≤10%.Use glass or ceramic microspheres, microsphere must be ordered from supplier, and arranges the patient to treat, and can obtain suitable decay by the alignment time like this.This kind microsphere is encapsulated in the sealing phial in the thick lucite column of 1.2cm, sends.

[195] when receiving the transmission of manufacturer, use radiation survey meter (radiation survey meter), at the fixed range of 30cm, measure from the outer bremstrahlen of lucite column, examine the activity of microsphere.Consistency detection (consistency check) and the baseline value before the program of inculcating served as in this measurement.After inculcating, microsphere bottle and delivery catheter and line are put into the big lucite container of same thickness, and measure in same distance.Inculcate the nominal standard dose that value that fore-and-aft survey obtains has provided microparticle percentage ratio and just has been sent to the patient.

[196] screening sequence particularly a security feature of MAA scanning be to prevent that the radiation of high dose level from entering/or appear in intestines and stomach or the lung.Because shunting is not easy to see that MAA scanning is used to assess the shunting degree in angiography, CT or MRI.Yet the potential principle of relevant MAA is that because the cause of its size, it will stimulate the deposition of glass microspheres.Yet because the proportion of glass particle is far longer than saline or MAA granule, this lifting manipulation does not obtain consistent the approval in this area.In fact, when MAA demonstrates less than 15% diverting coefficient, use in the pro-clinical trial phase among the patient of these glass spheres serious pulmonary's toxicity not occur.---screening shunting---realize easily, but albumin coating of particles and weight is not the spitting image of glass microspheres to also have the purpose of MAA.

[197] dosimetry can not be implemented with inculcating these class methods at present; But, reported the gross activity of the spheroid of inculcating.The limited effort of being done for exploitation dosimetry model [20,45-47] has comprised pathology sampling and nuclear medical image in the past, but does not comprise modern radiation therapy method.The applicant provides dose volumes (3D isodose volumes) such as the dosage-volume rectangular distribution function figure of microsphere treatment and 3D for the first time.[30] these volumes are based on the MAA data.

The use of microparticle and medication

[198] this method provides control to be delivered to the accumulated dose of certain position and has controlled three kinds of methods to the exposure in other zones of health simultaneously.At first, isotopic total quantity can change.The second, select the isotopic half-life, this provides the upper limit of application dose.The 3rd, can be controlled at the local radioisotopic life-span of transmitting in the storage area (local deliverydepot).

[199] one aspect of the present invention relates to the method for thromboembolism, comprises the suppository compositions is sent to blood vessel, and to be full of or occluding vascular and/or promote grumeleuse to form, like this, the blood flow by blood vessel reduces or stops.

[200] the present invention also relates to and the blended treatment of imaging radiosiotope effector radiosiotope effector, wherein treatment is stored on the identical microparticle carrier with radionuclide with imaging or diagnosis with radionuclide.

[201] also have, the present invention relates to directed microparticle structure (targeted microparticle constructs), wherein, 90Y and indium-111 or technetium isotope can mix in same microparticle structure.

[202] the present invention also provides the method for people or other mammalian subject being carried out radiation therapy, and it comprises to the patient uses radiation emission radionuclide.Preferably, β-radiation emission radionuclide is a 90Y.

[203] in preferred embodiments, treatment of the present invention comprises the primary hepatocarcinoma or the secondary liver cancer of treatment cancer or tumor, particularly patient.

[204] microparticle treatment administration is carried out in outpatient service angiography chamber (outpatient angiography suite), wherein has the radiation doctor to check and leaves the personnel of therapeutic room (treatment suite), and monitor any possible pollution.Before treatment, the ground of angiography chamber covers curtain greatly, to prevent any potential pollution.Collect all polluters (for example curtain, glove, shoe cover etc.), and fall as the radiation waste disposal.

[205] the interventional radiology worker puts into suitable Hepatic artery by patient's femoral artery with the intubate percutaneous.Doctor, radiation oncology worker and interventional radiology worker confirm independently patient's evaluation be correct, with the dosage that transmits, wait leaf or the whole liver of being inculcated and the activity of the microsphere waiting to be inculcated.The radiation oncology worker that enforcement is inculcated checks the intubate position with the interventional radiology worker.What microparticle was set inculcates flow velocity (usually 1-2cc/ second), flows backwards back in the arteria gastrica supply (gastric artery supply) to avoid spheroid.The microsphere bottle is connected to doser, microsphere is delivered to patient's intubate from bottle.When radiation oncology worker inculcates each time, inculcate 10 continuously to 20cc.Radioactive exposure meter (radiation exposure meter) is placed on place near source bottle (source vial), with remaining activity in the assessment phial.The doctor uses directed GM enumerator (directional GM counter) to monitor the exposure situation of passing through whole system during inculcating.When obtaining the maximum activity transfer, he also tells radiation oncology worker.95% inculcate and expect that is higher than accumulated dose.Employed phial be connected intubate and be placed in the lucite jar, measure residual activity then.When receiving the source, the substantial activity that is sent to the patient is just by determine (same distance is carried out standardization and decay is revised) from the exposed amount of organic glass jar and the ratio from the exposed amount of microsphere phial.

[206] the microsphere infusion device has allowed microsphere is carried out safe transmission.Yet because the complexity of system has potential defective, this makes is inculcating saline into the microsphere chamber, removes the air in circuit, the useless bottle, and microsphere inculcated between the patient may produce mistake (miss-timing).If the dosage of a part flows in the useless bottle, way is fetched never again.If this thing happens, the patient may need to inculcate extra microsphere.Provide the company of this treatment product developing the alternative infusion device that will address this problem.

[207] all patients that accept the intervention radiation art recover from anesthesia in the room of oneself.Measure exposure in the place of distance patient liver certain distance, obtain measured value and determine that needs of patients avoids contacting with others' natural law of (＜3 feet).In certain embodiments, for example measured in back 3 days inculcating, measured in back 14 days inculcating for child and anemia of pregnant woman for the adult.Most patient can suture nearby find the femoral artery site, and therefore discharged (discharge) in about 2 hours after finishing inculcating possibly.

[208] offer medicine when supplying with when microsphere or other granules, have that can to cause producing best equally distributed size, shape and density in Target organ be favourable to the arterial blood of Target organ.If microsphere or granule skewness, and be the function of the absolute blood flow volume of conduct, their can accumulate in some zone with too much quantity so, and cause the excess radiation of focus area (focal areas).Show that when the arterial circulation of the liver of offeing medicine, the microsphere of the about 25-50 micron of diameter has best distribution characteristics (Meade, V.et al; Distribution of different sized microspheres in experimental hepatic tumours.Europ.J.Cancer ﹠amp; Clin.Oncol.1987,23:23-41).

[209], will need excessive microsphere or granule to send necessary radiation dose to Target organ so if microsphere or granule do not contain enough ionizing radiation.Show, if a large amount of microspheres is offerd medicine in the tremulous pulse supply of liver, they accumulate in the small artery (small arteries) towards tumor and block small artery so, rather than are evenly distributed in the capillary tube and precapillary arteriole of tumor.Therefore, it is favourable using the microsphere of minimum number, and the microsphere of minimum number will be evenly distributed in the tumor circulation blood vessel network.

[210] similarly, if microsphere or granule are too dense or too heavy, so they will be not can be in Target organ uniform distribution, and will be in the part of liver, and that part does not contain cancer with excessive concentrations build-up.Show that in the time of in being injected into the supply of liver tremulous pulse, the solid-state heavy distribution of microsphere in the liver soft tissue is relatively poor.This then reduced effective radiation on the cancer that arrives in the Target organ, thereby reduced the ability of radiological predication fallout plot spheroid kill tumor cell.On the contrary, microsphere distributes in liver well.(Burton，M.A.et?al.；Selective?International?Radiation?Therapy；Distribution?of?radiation?in?the?liver.Europ.J.Cancer?Clin.Oncol.1989，25：1487-1491)。

[211] for the radiological predication fallout plot spheroid that successfully is used for treatment of cancer, the radiation of launching from microsphere be high-octane and short distance.This guarantees will deposit to the tissue that is close to around the microsphere from the energy that microsphere is launched, and is not deposited in the non-destination organization.Have and manyly can be incorporated into the radionuclide that microsphere is used for SIRT.Although other isotopes such as iodine also can use, be particularly suitable for this form treatment be unsettled isotope yttrium (Y-90) and phosphorus (P-32).90Y is the unsettled isotope of yttrium-89, and it can preparation gets in the neutron beam by stable yttrium-89 is placed on.The 90Y that produces decays, and the half-life is 64 hours, launches the pure β radiation of high energy simultaneously.

[212] therefore, microparticle of the present invention be applied be used for the treatment of, diagnosis and/or imaging purpose, they have low-density with respect to pure yttrium, size about 20 to about 80 micrometer ranges, and be stable, therefore when people or other mammalian subject healths are given in dispensing, there is not radioactive substance to come out from the microparticle diafiltration.

[213] the chemical ruggedness of microparticle of the present invention increases compared with previous disclosed microparticle, and this is because when being applied, and microparticle of the present invention can not discharge a large amount of radiation emission radiosiotope in blood circulation.

[214] be sent in the live body for insoluble substance controlled doses, but material provides with the form that is contained in the quantitation in the bottle, and system is provided, be used for the entire content of mixing radioisotopic insoluble substance is washed into body by bottle.

[215] according in the selected bottle radioactivity---this is to determine by the initial measurement of radioactivity and isotopic natural half-life, by giving an entire contents in the bottle, can transmit the radioactivity of exact dose.

[216] by the radioactivity complex is directly imposed on damaging part by the blood vessel approach, the radioactivity complex can be as the internal radiation treatment, treatment hepatocarcinoma, rheumatoid arthritis or entity tumor are such as hepatocarcinoma, the brain cancer, breast carcinoma, ovarian cancer or similar disease.

[217] material and the method for occlusion body internal radiation hepatocarcinoma of the present invention.

[218] optionally, radiocurable method of the present invention can be applied to the accessibility any tumor of vascular catheterization.This technology can be applied to the tumor of height vascularization especially, or has the tumor that single domination arteries is supplied with (singledominant arterial vascular supply).Particularly, method of the present invention relate to renal cell carcinoma, hepatocarcinoma, sarcoma, head and neck cancer and central nerve neuroma treat, imaging and/or diagnosis.In specific embodiment, by being injected into the tremulous pulse of supporting tumor, many radiological predication fallout plot granules that will contain 90Y are administered to the patient.When microparticle is fixed on deposition position, at the local tumor volume (local tumorvolume) of deposition region by radiation.

[219] in certain embodiments, administering therapeutic is given patient, the patient who has cancer and/or tumor with diagnosis with the radiological predication fallout plot granule.A kind of method that the patient that suspection is had a tumor carries out cancer diagnosis comprises: in described patient's target location, give the patient many radiological predication fallout plot granules, the diameter of each in wherein said many radiological predication fallout plot granules about 5 to about 200 micrometer ranges, and right and wrong are biodegradable, and comprise core, at least a connection carrier that is positioned on the described core, wherein said connection carrier comprises biocompatible polymer, with at least a radiation treatment agent that is covalently bound to described connection carrier, wherein said radiation treatment agent comprises γ-emission radionuclide; Detect described many radiological predication fallout plot granules; With determine from described testing result whether the patient has tumor, wherein detect the described patient that described tumor just is diagnosed as cancer.

Imaging detects

[220] in the enforcement of a kind of embodiment of the present invention, after giving diagnostic agent, can carry out imaging.Collect then by light is delivered on the various structures, directly or indirectly observe these structures, can detect endoceliac tumor.As long as Non-ionizing radiation can be sent to these structures, and capture again, just can observe infringement at any body position from these structures.For example, the imaging technique of high-resolution, Noninvasive---positron emission tomography (PET) can be used from observer's class disease with antibody one of the present invention.In PET, the 511keV γ photon that produces during positron annihilation decay (positron annihilation decay) is detected.The similarly pre-targeting strategy (pre-targeting strategies) of PET---use fluoro-18 and gallium-68 to be described in United States Patent (USP) 6,187 respectively, 284 and U.S. serial 09/644,706 in.The method that is described in these applications can easily be made amendment being used for the present invention, so they incorporate this paper into by reference in its entirety.

[221] consider to use the granule with multiple radionuclide, wherein one or more radionuclides are attached on core and/or the connection carrier.

[222] of the present invention one independently embodiment be on single microparticle, to use multiple radionuclide.Such as core, at least two kinds of radiation treatment agent are attached on the described core.Described at least two kinds of radiation treatment agent can be independently selected from treats with radionuclide and imaging or diagnosis radionuclide.These at least two kinds of radiation treatment agent can be independently selected from α-emission radionuclide, beta-emitting radionuclide and/or γ-emission radionuclide.

[223] in one embodiment, at least two kinds of combinations that the radiation treatment agent is beta-emitting radionuclide and γ-emission radionuclide.For example, beta-emitting radionuclide---it is that radionuclide is used in treatment, and γ-emission radionuclide---it is imaging or diagnosis radionuclide.Use radionuclide such as 90Y as treatment, indium-111 and/or Tc-99m are as imaging or diagnosis radionuclide.

[224] in one embodiment, the core right and wrong are ceramic and the nonradioactive labeling.Core can be a polymer, such as polyacrylic acid; the ethene-vinyl acetate polymer; the cellulose acetate of acyl substituted; polyurethane; polystyrene; polrvinyl chloride; polyvinyl fluoride; poly-(ethylene imidazoles); chlorosulfonic acid ester polyolefin; polyoxyethylene; its mixture; with its copolymer; poly-phosphazine; poly-(vinyl alcohol); polyamide; Merlon; polyalkylene; polyacrylamide; poly alkylene glycol; polyalkylene oxide; polyalkylene terephthalates; polyvinylether; polyvinyl ester; polyvinyl halides; polyvinylpyrrolidone; poly-Acetic acid, hydroxy-, bimol. cyclic ester; polysiloxanes and its copolymer; alkylcellulose; hydroxy alkyl cellulose; cellulose ether; cellulose esters and/or NC Nitroncellulose.

[225] described at least two kinds of radiation treatment agent can be passed through covalent bond, are attached to described core separately.

[226] in one embodiment, granule can diafiltration not go out radionuclide.

[227] granule with multiple radionuclide can be used for these methods, comprises radiotherapy and imaging and/or diagnosis.Application with microparticle of two or three isotope complex makes it possible to carry out in real time and treatment back diagnosing image.

[228] can measure γ-radiation, to determine the position of microparticle in the patient.

Embodiment

[229] following embodiment is used for exemplary illustrated the preferred embodiments of the invention.According to disclosure of the present invention, all disclosed compositionss and method can be produced and carry out, and need not extra experiment.

[230] although the compositions and methods of the invention are described according to preferred embodiment, it will be apparent for a person skilled in the art that, can compositions and/or the method for describing herein be changed, and can not break away from notion of the present invention, spirit and scope.

[231] more specifically, it is evident that, some chemically with physiology on relevant reagent can replace herein the reagent of describing, can obtain same or similar result simultaneously.

[232] this kind of all that it will be apparent to those skilled in the art similarly substitutes and modifies and all think within spirit of the present invention, scope and notion.

[233] Embodiment 1: the preparation with PMMA microparticle of functionalized surface

[234] PMMA is a hydrophobic polymer, but its surface chemically is being inert, does not contain the functional group that is suitable for direct coupling bioactive substance.PMMA also has low toleration to organic reagent and solvent.A kind of method that PMMA microparticle pearl is carried out the functionalization effect is the methyl ester group effect of being hydrolyzed (Holmberg and Hyden, 1985) to the PMMA surface.This makes can adhere to carrier molecule, and as dendritic macromole, it contains the amino-functional group.Because dendritic macromole has a plurality of functional groups on its surface, the microparticle surface of resulting modified will provide the surface of the avtive spot with high concentration, be used to carry out labelling thereby can further adhere to chelating agen.Material comprises the PMMA microparticle, 25 μ diameters, PAMAM-NH ₂Poly-(amide amine) dendritic macromole (Sigma), p-NO ₂-Bz-DOTA, p-NH ₂-Bz-DOTA (Macrocyclic, TX, USA), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide EDAC (Fluka).The hydrolysis of PMMA ester group: to the methanol that is cooled to 0 ℃: in the PMMA microparticle suspension in the water (1: 1), under agitation dropwise add excessive 1 (N) NaOH.Reactant mixture stirred 1.5 hours at 0 ℃, stirred 16 hours at 40 ℃.Microparticle is with 0.1 (N) HC1 and methanol: water (1: 1) washing, centrifugal, turned letter liquid is suspended among the PBS (7.4) again, obtains PMMA-COOH.

[235] Embodiment 2: the activation of PMMA-COOH spheroid and be coupled to the PAMAM dendritic macromole

[236] as above the PMMA-COOH microparticle (10mg) of preparation washs 2 times in 10ml PBS.(pellet) is suspended among the PBS of 10ml again with precipitate, and adds the EDAC of 100mg, mixes.Reactant mixture added the dendritic macromole (PAMAM-NH that is among the 5ml PBS then at stirring at room 15-30 minute ₂) (10X).Make to be reflected at and proceed 30 minutes to 1 hour in the room temperature.Microparticle (PMMA-PAMAM-NH ₂) wash 2 times with PBS, and be suspended among the PBS again.

[237] reaction/hydrolysis rate of 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDAC) increases with low pH.The optimized buffer scope of reaction is pH 4.5-7.5.In one step, carry out the COOH group activation and and the NH of EDAC mediation ₂The coupling of-functional group usually is difficult for the bigger molecule of coupling, yet is effective for littler molecule as hapten and steroid.EDAC and carboxyl reaction obtain intermediate product o-acylisourea.This intermediate product and amine reaction form the bonded conjugate of peptide.Yet hydrolysis takes place in this intermediate product in aqueous solution, and therefore, stability is normally essential, and this can realize by adding N-hydroxy-succinamide.In order to reduce coupling between the dendritic macromole, the concentration of PAMAM should excessively greatly (also see also Holmberg K, Hyden H.Methods of immobilization of proteins topolymethacrylate.Preparative Biochemistry, 15 (5): 309-319 (1985)).

[238] Embodiment 3: the DOTA chelating agen is attached to dendritic macromole so that transmit yttrium

[239] to PMMA-PAMAM-NH ₂In the PBS suspension of microparticle, stirring and dropwise adding p-NO ₂The PBS solution of-Bz-DOTA.At room temperature, reactant mixture stirred 16 hours.After the stirred overnight, pearl washs 2 times with PBS, and is suspended in the buffer again.Alternately, make to use the same method, with p-NH ₂(USA) reaction also can directly be coupled to the PMMA-COOH microparticle with DOTA to-Bz-DOTA for Macrocyclic, TX.

[240] Embodiment 4: the mensuration of microparticle chelating agen concentration

[241] under the condition that the yttrium-89 of variable quantity exists, use the 90Y (100 μ Ci) of constant basis, measure the concentration of chelating agen, total yttrium concentration in 20-1000 μ M scope, wherein, yttrium 90 ≈ 1 μ m.Briefly, 90Y (20mCi is in the 50mMHC1 of 100 μ l) or the Yttrium chloride(Y2Cl6) in the HCl of 50mM-89 dilute with the 50mM HCl of 50 μ L and the 50mM sodium citrate of 350 μ L.In typical mensuration, yttrium-89 solution (100-200 μ Ci, 4 μ l), yttrium-89 solution (5 μ L) contains the 100mM histidine buffering liquid (25 μ L) of 10mM sodium citrate pH 7.4, water (16 μ l); The microparticle of 2mg/mL in the 50mM histidine buffering liquid (50 μ l), this 50mM histidine buffering liquid contains the sodium citrate of 5mM pH7.4.The yttrium that is attached on the granule is measured with above-described method, by bonded yttric percentage ratio yttrium concentration is mapped, and is extrapolated by this figure and determines chelating agen concentration.Optionally, arrive microparticle, add 90Y then, measure chelating agen concentration by the yttrium-89 that adds varied number.

[242] these titration experiments are crossed adding " cold (cold) " yttrium-89 to microparticle, add the 90Y isotope then, measure the amount of the 90Y that is attached to microparticle and implement.Along with yttrium-89 quantity increases, 90Y in conjunction with reducing, this is because the binding site on the microparticle is saturated, cause 90Y in conjunction with repressed cause.No longer include bonded the time at 90Y, yttrium-89 concentration equals the concentration in chelating site.Optionally, titration is such carrying out, and the 90Y of trace is joined yttrium-89, and this mixture that contains excessive yttrium-89 is joined microparticle.The concentration of the DOTA chelating agen that exists in solution, measure conforms to the concentration that calculates.For the microparticle of the DOTA chelating agen that contains 1 and 5 molar percentages, the concentration 0.11 that calculates conforms to the DOTA chelating agen of concentration 0.5 that measures and 0.1mM with 0.55mM very much.

[243] Embodiment 5: Y-90 is attached to microparticle

[244], the yttrium-89 of natural generation and isotope 90Y and indium-111 are attached to microparticle by being chelated to the DOTA chelating agen.Labeling effciency is greater than 98%, and the labelling capacity of 90Y is the about 10mCi of every mg granule.In acetate, MES and HEPES buffer, detect the influence of pH to the 90Y joint efficiency, the result is in pH 5-7, in conjunction with not influenced by pH.Microparticle also can be used indium-111 labelling, and indium-the 111st is usually used in γ-emitting isotope that in-vivo imaging is studied.In the carrying capacity level of every mg microparticle 50-500 μ Ci, measurement markers efficient.Because the cause that the melts combine capacity is high, microparticle are also simultaneously in conjunction with 90Y and indium-111.According to every kind of isotope of every mg microparticle is 0.1 or 1mCi, carries out follow-up loading experiment (sequential loadingexperiments), measure resulting two kinds isotopic in conjunction with percentage ratio.

[245] Embodiment 6: by stability---the histidine Attack Research (Histidinechallenge studies) of the microparticle of labelling Y-90

[246] chlorination 90Y in 50mM HC1 or indium chloride-111 (10-20mCi) dilute with 50mM citric acid (pH4), obtain the solution of 50mCi/mL.90 μ L microparticle solution in the histidine buffering liquid of 50mM add the 10 μ L isotope solution that contain 100-200 μ Ci, and described histidine buffering liquid contains the 5mM citrate of pH 7.Solution room temperature incubation 30 minutes, is joined l00K MWCO rotating filter cartridge (spinfilter cartridge) (Nanosep) then, and rotating filter cartridge is placed in the table model high speed centrifuge (table top centrifuge).After 3000rpm rotation 90-120 minute, use Capintec CRC-15R dose calibrator (dosecalibrator) that isotope is quantized.The filtration fraction that contains microparticle-isotope complex of tube is removed, remaining unconjugated isotope is quantized.These values are used to the percentage ratio of the metal of calculations incorporated, or the bonded isotopic quantity of every mg microparticle.

[247] Embodiment 7: the vitro stability of microparticle-isotope conjugate

[248] in order to estimate the stability of conjugate in serum, the microparticle 90Y complex of chelating agen that will contain 5 molar percentages at 37 ℃ of incubations in rabbit anteserum.Solution room temperature incubation 30 minutes, is joined 100KMWCO rotating filter cartridge (Nanosep) then, and rotating filter cartridge is placed in the table model high speed centrifuge.After 90-120 minute, use Capintec CRC-15R dose calibrator that isotope is quantized in the 3000rpm rotation.Remove the tube filtration fraction that contains microparticle-isotope complex, remaining unconjugated isotope is quantized.These values are used to the percentage ratio of the metal of calculations incorporated, or the bonded isotopic quantity of every mg microparticle.

[249] Embodiment 8: the DOTA chelating agen is carried out specificity Y-90 labelling

[250] concentration at DOTA-fat is under the situation of 0.56-560 μ M, with weak chelating agent citrate and strong chelating agent diethylamine pentaacetic acid (DTPA) incubation microparticle 90Y complex, has proved the specific marker of the DOTA on vesicle (vesicles).Metal composite is stable under the condition that the 500mM citrate exists, and under the condition that 1mM DTPA exists, after 30 minutes, about 90% yttrium remains to microparticle 90Y complex incubation.

[251] the invention provides the implementation method of in situ preparation reagent, like this, it can be optimized to satisfy patient dose requirement (patient dose requirements) and medical facilities and personnel placement.In addition, the present invention has following advantage: the means of using γ, β and alpha activity nucleic to carry out radiological measuring and/or treatment i) are provided, and γ, β and alpha activity nucleic use separately on same granule or unite use; The hands section of the tissue dose that accurate measurement bio distribution ii) is provided and has been applied; Do not need this product to produce in the nuclear reactor outside the field of employment in advance, thereby farthest be applicable to individual, university or public administration (managed-care) medical centre all over the world.

[252] the attracting especially advantage of microparticle of the present invention is, they provide the intra-arterial of blood flow distribution (blood flowdistribution) to detect, and can be used for any Target organ (it needs radiation therapy to destroy, to kill, to suppress abnormal cell and/or the death of promotion abnormal cell) or endovascularly can carry out radiation therapy near tumor (intravascularly accessible tumor).The treatment that organ that can contact blood vessel with α or β emission radionuclide or tumor are carried out, allowing needs the patient of radiation therapy to finish radiation therapy by a plurality of microparticles of the present invention are applied to.In embodiment optionally, microparticle also comprises diagnosis or imaging radionuclide.

The list of references of quoting

[253]1.Kemeny?N，Huang?Y，Cohen?AM，et?al.Hepatic?Arterial?Infusion?ofChemotherapy?After?Resection?of?Hepatic?Metastases?From?Colorectal?Cancer.NewEngland?Journal?of?Medicine?1999；341：2039-2048.

[254]2.Fong?Y，Blumgart?LH，Cohen?AM.Surgical?treatment?of?colorectal?metastasesto?the?liver.CA?Cancer?J?Clin?1995；45：50-62.

[255]3.El-Serag?HB，Mason?AC.Rising?incidence?of?hepatocellular?carcinoma?in?theUnited?States.N?Engl?J?Med?1999；340：745-50.

[256]4.Lawrence?TS，Kessler?ML，Robertson?JM.Conforma?high-dose?radiation?plusintraarterial?floxuridine?for?hepatic?cancer.Oncology(Huntingt)1993；7：51-7；discussion?57-8，63.

[257]5.Lawrence?TS，Kessler?ML，Robertson?JM.3-D?conforma?radiation?therapy?inupper?gastrointestinal?cancer.The?University?of?Michigan?experience.Front?Radiat?TherOncol?1996；29：221-8.

[258]6.Lawrence?TS，Dworzanin?LM，Walker-Andrews?SC，et?al.Treatment?of?cancersinvolving?the?liver?and?porta?hepatis?with?external?beam?irradiation?and?intraarterialhepaticfluorodeoxyuridine.Int?J?Radiat?Oncol?Biol?Phys?1991；20：555-61.

[259]7.McGinn?CJ，Ten?Haken?RK，Ensminger?WD，WalkerS，Wang?S，Lawrence?TS.Treatment?of?intrahepatic?cancers?with?radiation?doses?based?on?a?normal?tissuecomplication?probability?model.J?Clin?Oncol1998；16：2246-52.

[260]8.McGinn?CJ，Lawrence?TS.Clinical?Results?of?the?Combination?of?Radiationand?Fluoropyrimidines?in?the?Treatment?of?Intrahepatic?Cancer?Semin?Radiat?Oncol1997；7：313-323.

[261]9.Ariel?IM.Treatment?of?inoperable?primary?pancreatic?and?liver?cancer?by?theintra-arterial?administration?of?radioactive?isotopes(Y90radiating?microspheres).AnnSurg?1965；162：267-78.

[262]10.Ariel?IM，Pack?GT.Treatment?of?inoperable?cancer?of?the?liver?byintra-arterial?radioactive?isotopes?and?chemotherapy.Cancer?1967；20：793-804.

[263]11.Simon?N，Warner?RRP，Baron?MG，Rudavsky?AZ.Intra-arterial?Irradiation?ofCarcinoid?Tumors?of?the?Liver.The?American?Journal?of?Roentgenology，RadiumTherapy?and?Nuclear?Medicine?1968；102：552-561.

[264]12.Caldarola?L，Rosa?U，Badellino?F.Preparation?of?32P?Labelled?ResinMicrospheres?For?Radiation?Treatment?of?Tumors?By?Intraarterial?Injection.PanminervaMed?1965；7：102.

[265]13.Blanchard?RJ，Grotenhuis?I，LaFave?JW.Treatment?of?Experimental?Tumors：Utilization?of?Radioactive?Microspheres.Archives?of?Surgery?1964；89：406.

[266]14.Blanchard?RJ，LaFave?JW，Kim?YS.Treatment?of?Patients?with?AdvancedCancer?Using?Y-90microspheres.Cancer?1965；18：375.

[267]15.Kim?YS，LaFave?JW，MacLean?LD.The?Use?of?Radiating?Microspheres?in?theTreatment?of?Experimental?and?Human?Malignancy.Surgery?1962；52：220.

[268]16.Blanchard?RJW.Treatment?of?Liver?tumours?with?yttrium-90microspheres.The?Canadian?Journal?of?Surgery?1983；26：442-443.

[269]17.Mantravadi?RV，Spigos?DG，Tan?WS，Felix?EL.Intraarterial?yttrium?90in?thetreatment?of?hepatic?malignancy.Radiology?1982；142：783-6.

[270]18.Ariel?IM，Padula?G.Treatment?ofasymptomatic?metastatic?cancer?to?the?liverfrom?primary?colon?and?rectal?cancer?by?the?intraarterial?administration?ofchemotherapy?and?radioactive?isotopes.J?Surg?Oncol?1982；20：151-6.

[271]19.Grady?ED.Internal?radiation?therapy?of?hepatic?cancer.Dis?Colon?Rectum1979；22：371-5.

[272]20.Blanchard?RJ，Morrow?IM，Sutherland?JB.Treatment?of?liver?tumors?withyttrium-90microspheres?alone.Can?Assoc?Radiol?J?1989；40：206-10.

[273]21.Burton?MA，Gray?BN，Jones?C，Coletti?A.Intraoperative?dosimetry?of?90Y?inliver?tissue.Int?J?Rad?Appl?Instrum?B?1989；16：495-8.

[274]22.Anderson?JH，Goldberg?JA，Bessent?RG，et?al.Glass?yttrium-90microspheresfor?patients?with?colorectal?liver?metastases.Radiother?Oncol?1992；25：137-9.

[275]23.Shepherd?FA，Rotstein?LE，Houle?S，Yip?TC，Paul?K，Sniderman?KW.A?phaseI?dose?escalation?trial?of?yttrium-90microspheres?in?the?treatment?of?primaryhepatocellular?carcinoma.Cancer?1992；70：2250-4.

[276]24.Yan?Zp，Lin?G，Zhao?HY，Dong?YH.An?experimental?study?and?clinical?pilottrials?on?yttrium-90?glass?microspheres?through?the?hepatic?artery?for?treatment?ofprimary?liver?cancer.Cancer?1993；72：3210-5.

[277]25.Andrews?JC，Walker?SC，Ackermann?RJ，Cotton?LA，Ensminger?WD，ShapiroB.Hepatic?radioembolization?with?yttrium-90containing?glass?microspheres：preliminary?results?and?clinical?follow-up[see?comments].J?Nucl?Med?1994；35：1637-44.

[278]26.Lau?WY，Leung?WT，Ho?SK，et?al.Treatment?of?inoperable?hepatocellularcarcinoma?with?intrahepatic?arterial?yttrium-90microspheres：a?phase?I?and?II?study.BrJ?Cancer?1994；70：994-9.

[279]27.Leung?TW，Lau?WY，Ho?SK，et?al.Radiation?pneumonitis?after?selectiveinternal?radiation?treatment?with?intraarterial?90yttrium-microspheres?for?inoperablehepatic?tumors.Int?J?Radiat?Oncol?Biol?Phys?1995；33：919-24.

[280]28.Leung?WT，LauWY，Ho?SK，et?al.Measuring?lung?shunting?in?hepatocellularcarcinoma?with?intrahepatic-arterial?teclmetium-99m?macroaggregated?albumin.J?NuclMed?1994；35：70-3.

[281]29.Kennedy?AS，Murthy?R，Sarfaraz?M，et?al.Outpatient?Hepatic?ArteryBrachytherapy?for?Primary?and?Secondary?Hepatic?Malignancies.Radiology?2001；221P：468.

[282]30.Kennedy?AS，Murthy?R，Van?Echo?DA.Preliminary?Results?of?OutpatientHepatic?Artery?Brachytherapy?for?Colorectal?Hepatic?Metastases.European?Journal?ofCancer?2001；37：289.

[283]31.Kennedy?AS，Murthy?R，Kwok?Y，al.e.Hepatic?Artery?Brachytherapy?forUnresectable?Hepatocellular?Carcinoma：An?Outpatient?Treatment?Approach.Proceedings?of?the?12th?International?Congress?on?Anti-Cancer?Treatment?2002；1：198-199.

[284]32.Kennedy?AS，Salem?R.Comparison?of?two?90Yttrium?microsphere?agents?forhepatic?artery?brachytherapy.Proceedings?of?the?14th?International?Congress?onAnti-Cancer?Treatment?2003：156.

[285]33.Kennedy?AS，Van?Echo?DA，Murthy?R，al.e.Colorectal(CRC)livermetastases?and?Hepatocellular?carcinoma(HCC)treated?with?outpatient?hepatic?arterybrachytherapy，TheraSphere：Imaging?response?and?toxicity.Int?J?Cancer?2002；S?13：226-227.

[286]34.Kennedy?AS，Van?Echo?DA，Murthy?R，al.e.Hepatic?artery?brachytherapy?forneuroendocrine?carcinoma.Regulatory?Peptides?2002；108：32.

[287]35.Murthy?R，Kennedy?AS，Coldwell?D，al.e.Technical?aspects?of?TheraSphere(TS)infusion.J?Vase?Interv?Radiol?2002；13：S2.

[288]36.Murthy?R，Kennedy?AS，Tucker?G，al.e.Outpatient?trans?arterial?hepatic′lowdose?rate′(TAH-LDR)brachytherapy?for?unresectable?hepatocellular?carcinoma.Proceedings?of?American?Association?for?Cancer?Research?2002；43：485.

[289]37.Murthy?R，Line?BR，Kennedy?AS，al.e.Clinical?utility?of?Brehmstralung?scan(BRM-Scan)after?TheraSphere(TS).J?Vase?Interv?Radiol?2002；13：S2.

[290]38.Sarfaraz?M，Kennedy?AS，Cao?ZJ，Li?A，Yu?C.Radiation?Dose?Distribution?inPatients?Treated?with?Y-90Microspheres?for?Non-Resectable?Hepatic?Tumors.International?Journal?of?Radiation?Biology?and?Physics?2001；51：32-33.

[291]39.Van?Echo?DA，Kennedy?AS，Coldwell?D.TheraSphere(TS)at?143Gy?mediandose?for?mixed?hepatic?cancers；feasibility?and?toxicities.Amer?Soc?Clin?Oncol?2001；260a：1038.

[292]40.Coldwell?D，Kennedy?AS，Van?Echo?DA，al.e.Feasibility?of?treatment?ofhepatic?tumors?utilizing?embolization?with?yttrium-90glass?microspheres.J?Vase?IntervRadiol?2001；12：S113.

[293]41.Wright?AA，Jenkins?JJ，Lodge?MA，Murthy?R，Kennedy?AS，Line?BR.Predictive?factors?in?90Y?microsphere?therapy?for?shunt?fraction.J?Nuclear?Medicine2002；43：103P.

[294]42.Mourtzikos?K，Lodge?MA，Maragh?M，et?al.Measurement?ofHepatopulmonary?shunt?fraction?prior?to?90Y?microsphere?treatment?of?hepaticmalignancy.J?Nuclear?Medicine?2002；43：317P.

[295]43.Hisley?C，Lodge?MA，Kennedy?AS，Mourtzikos?K，Line?BR.Estimation?of90Y?TheraSphere?Treatment?Effectiveness?by?Statistical?Segmentation?of?Hepatic?TissueVolumes.J?Nuclear?Medicine?2002；43：103P.

[296]44.

UO，Casillas?S，Dietz?DW，et?al.Hepatic?tumor?radioembolization?in?arat?model?using?radioactive?rhenium(186RE/188RE)glass?microspheres.Int?J?RadiatOncol?Biol?Phys?1999；44：189-199.

Claims

1. microparticle comprises:

Core;

Be positioned at least a connection carrier on the described core, wherein said connection carrier comprise biocompatible polymer and

Be covalently bonded at least a radiation treatment agent of described connection carrier;

The diameter of wherein said microparticle is about 5 to about 200 micrometer ranges, and described microparticle right and wrong are biodegradable.

2. granule as claimed in claim 1, wherein said at least a radiation treatment agent is α-emission radionuclide, beta-emitting radionuclide or γ-emission radionuclide.

3. granule as claimed in claim 1, wherein said at least a radiation treatment agent comprises α-emission radionuclide and beta-emitting radionuclide.

4. granule as claimed in claim 1, wherein said at least a radiation treatment agent comprises beta-emitting radionuclide and γ-emission radionuclide.

5. granule as claimed in claim 1, wherein said at least a radiation treatment agent comprises α-emission radionuclide and γ-emission radionuclide.

6. granule as claimed in claim 1, wherein said at least a radiation treatment agent comprise treats with radionuclide and imaging or diagnosis radionuclide.

7. granule as claimed in claim 6, wherein said treatment radionuclide is a beta-emitting radionuclide, described imaging or diagnosis are γ-emission radionuclides with radionuclide.

8. granule as claimed in claim 6, wherein said treatment is selected from Y-90, Bi-213, At-211, I-123, I-125, I-131, At-211, Cu-67, Sc-47, Ga-67, Rh-105, Pr-142, Nd-147, Pm-151, Sm-153, Ho-166, Gd-159, Tb-161, Eu-152, Er-171, Re-186 and Re-188 with radionuclide.

9. granule as claimed in claim 6, wherein said imaging or diagnosis are selected from Tc-99m, In-111, Ga-67, Rh-105, I-123, Nd-147, Pm-151, Sm-153, Gd-159, Tb-161, Er-171, Re-186, Re-188 and Tl-201 with radionuclide.

10. granule as claimed in claim 6, wherein said treatment comprises 90Y with radionuclide, described imaging or diagnosis comprise indium-111 or Tc-99m with radionuclide.

11. granule as claimed in claim 1, wherein said radiation treatment agent is radionuclide or radiopharmaceutical.

12. granule as claimed in claim 11, wherein said radionuclide is selected from iridium, radium, caesium, phosphorus, yttrium, rhenium, actinium, bismuth, astatine, technetium, indium, iodine, and carbon, nitrogen, fluorine, sodium, magnesium, aluminum, silicon, potassium, vanadium, manganese, gallium, niobium, iodine, plumbous, Y-90, Bi-213, At-211, I-123, I-125, I-131, At-211, Cu-67, Sc-47, Ga-67, Rh-105, Pr-142, Nd-147, Pm-151, Sm-153, Ho-166, Gd-159, Tb-161, Eu-152, Er-171, Re-186, Re-188, Tc-99m, In-111, Ga-67, Rh-105, I-123, Nd-147, Pm-151, Sm-153, Gd-159, Tb-161, Er-171, Re-186, Re-188 and T1-201.

13. granule as claimed in claim 1, wherein said radiation treatment agent is a 90Y.

14. granule as claimed in claim 1, wherein said radiation treatment agent is covalently bound to described connection carrier by one or more spacer groups or chelating agen group.

15. granule as claimed in claim 1, wherein said radiation treatment agent is covalently bound to described connection carrier by the chelating agen group.

16. granule as claimed in claim 15, wherein said chelating agen group is to be selected from least a in the following substances: cyclohexyl diethylene-triamine pentaacetic acid part (CHX-DTPA), diethylene-triamine pentaacetic acid (DTPA), ethylenediaminetetraacetic acid (EDTA), 1,4,7,10-tetraazacyclododecanand-N, N ', N, " N " ' tetraacethyl (DOTA), tetraazacyclododecane tetradecane-N, N "; N " N " tetraacethyl (TETA); cyclohexyl 1; 2-ethylenediamine tetraacetic acid (EDTA) (CDTA); ethylene glycol-O; O '-two (2-aminoethyl)-N; N, N ', N '-four-acetic acid (EGTA), N, N-two (acrinyl)-ethylenediamine-N, N '-oxalic acid (HBED), triethylenetetraaminehexaacetic acid (TTHA), hydroxyethyl diamine triacetic acid (HEDTA), HEDP (HEDP), dimercaptosuccinic acid (DMSA), diethylenetriamines tetramethylene see acid (DTTP) and 1-(p-ammonia benzyl)-DTPA, 1,6-diamino hexane N, N, N ', N '-tetraacethyl, DPDP and ethylene (oxygen ethylene itrile group)-tetraacethyl.

17. granule as claimed in claim 15, wherein said radiation treatment agent is a beta-emitting radionuclide, and described chelating agen group is DOTA.

18. granule as claimed in claim 17, wherein said beta-emitting radionuclide comprises 90Y.

19. granule as claimed in claim 1, wherein said covalent bond comprise difunctional junctional complex, carbodiimide condensation, or disulfide bond.

20. comprising, granule as claimed in claim 1, wherein said core be selected from following polymer: poly-(methyl methacrylate); polyacrylate; the ethene-vinyl acetate polymer; the cellulose acetate of acyl substituted; polyurethane; polystyrene; polrvinyl chloride; polyvinyl fluoride; poly-(ethylene imidazoles); chlorosulfonic acid ester polyolefin; polyoxyethylene; their mixture; with their copolymer; poly-phosphazine; poly-(vinyl alcohol); polyamide; Merlon; polyalkylene; polyacrylamide; poly alkylene glycol; polyalkylene oxide; polyalkylene terephthalates; polyvinylether; polyvinyl ester; polyvinyl halides; polyvinylpyrrolidone; poly-Acetic acid, hydroxy-, bimol. cyclic ester; polysiloxanes; their copolymer; alkylcellulose; hydroxy alkyl cellulose; cellulose ether; cellulose esters; and NC Nitroncellulose.

21. granule as claimed in claim 1, wherein said at least a connection carrier is to be selected from linear polymer, ramose polymer and dendritic.

22. granule as claimed in claim 1, wherein said at least a connection carrier comprises dendritic macromole.

23. granule as claimed in claim 22, wherein said dendritic macromole comprises disulfide bond in its core.

24. granule as claimed in claim 22, wherein said dendritic macromole have the final exterior layer that is added medicated cap by active group.

25. granule as claimed in claim 24, wherein said active group comprises amine groups or carboxylic group.

26. granule as claimed in claim 24, the wherein said active group at least a entity derivatization treatment that is selected from described radiation treatment agent, guiding entity and treatment entity.

27. granule as claimed in claim 22, wherein said dendritic macromole has at least one terminal functional groups, and this terminal functional groups can contact for chelating agen, and described chelating agen can interact with at least one functional group.

28. granule as claimed in claim 27, wherein said at least a functional group are to be selected from following at least a functional group: ester, ether, mercaptan, carbonyl, hydroxyl, amide groups, carboxyl and acid imide.

29. granule as claimed in claim 22, it comprises a plurality of dendritic macromoles, and wherein said dendritic macromole is a monodispersity.

30. granule as claimed in claim 1, wherein said connection carrier is a linear polymer.

31. granule as claimed in claim 1, wherein said particulate density 1 to 4gm/cm ³In the scope.

32. granule as claimed in claim 1, wherein said particulate density 1 to 2gm/cm ³In the scope.

33. granule as claimed in claim 1, wherein said granule further comprises second therapeutic agent, and wherein said at least a radiation treatment agent is first therapeutic agent, and described second therapeutic agent is the therapeutic agent that is different from first therapeutic agent.

34. granule as claimed in claim 33, wherein said second therapeutic agent are to be selected from following at least a material: metal-chelating complex, medicine, prodrug, radionuclide, boron additament, labelled compound, toxin, cytokine, lymphokine, chemotactic factor, immunomodulator, radiosensitizer, asparaginase, radiohalogen, chemotherapeutic agent and contrast agent.

35. a microparticle, it comprises:

Core; With

Be attached at least two kinds of radiation treatment agent of described core.

36. granule as claimed in claim 35, wherein said at least two kinds of radiation treatment agent are independently selected from α-emission radionuclide, beta-emitting radionuclide and γ-emission radionuclide.

37. granule as claimed in claim 35, wherein said at least two kinds of radiation treatment agent are independently selected from treatment radionuclide and guiding radionuclide.

38. granule as claimed in claim 37, wherein said treatment comprises beta-emitting radionuclide with radionuclide, and described guiding radionuclide comprises γ-emission radionuclide.

39. granule as claimed in claim 35, at least a beta-emitting radionuclide that comprises in wherein said at least two kinds of radiation treatment agent, and at least a γ-emission radionuclide that comprises in described at least two kinds of radiation treatment agent.

40. granule as claimed in claim 39, wherein said beta-emitting radionuclide comprises 90Y, and described γ-emission radionuclide comprises indium-111 or Tc-99m.

41. granule as claimed in claim 35, wherein said core is inactive.

42. comprising, granule as claimed in claim 35, wherein said core be selected from following polymer: poly-(methyl methacrylate); polyacrylate; the ethene-vinyl acetate polymer; the cellulose acetate of acyl substituted; polyurethane; polystyrene; polrvinyl chloride; polyvinyl fluoride; poly-(ethylene imidazoles); chlorosulfonic acid ester polyolefin; polyoxyethylene; their mixture; with their copolymer; poly-phosphazine; poly-(vinyl alcohol); polyamide; Merlon; polyalkylene; polyacrylamide; poly alkylene glycol; polyalkylene oxide; polyalkylene terephthalates; polyvinylether; polyvinyl ester; polyvinyl halides; polyvinylpyrrolidone; poly-Acetic acid, hydroxy-, bimol. cyclic ester; polysiloxanes; their copolymer; alkylcellulose; hydroxy alkyl cellulose; cellulose ether; cellulose esters; and NC Nitroncellulose.

43. granule as claimed in claim 35, wherein said core comprise poly-(methyl methacrylate) or polystyrene.

44. granule as claimed in claim 35, wherein said at least two kinds of radiation treatment agent are attached to described core separately by covalent bond.

45. a microparticle comprises:

Core;

Be attached at least a radioactivity guiding entity of described core, wherein said guiding entity comprises γ-emission radionuclide;

The diameter of wherein said microparticle is about 5 to about 200 micrometer ranges, and right and wrong are biodegradable.

46. granule as claimed in claim 45, described granule further comprise at least a radiation treatment entity, described treatment entity is made of beta-emitting radionuclide.

47. granule as claimed in claim 45, described granule further comprise at least a connection carrier that is positioned on the described core, wherein said connection carrier comprises biocompatible polymer.

48. a granular materials comprises microparticle, it has:

Core;

Be positioned at least a connection carrier on the described core, wherein said connection carrier comprises biocompatible polymer; With

Be covalently bound at least a radiation treatment agent of described connection carrier;

49. granular materials as claimed in claim 48, the diameter of wherein said microparticle is in the 8-100 micrometer range.

50. granular materials as claimed in claim 48, the diameter of wherein said microparticle is in the 25-50 micrometer range.

51. granular materials as claimed in claim 48, the diameter of wherein said microparticle is in the 20-30 micrometer range.

52. granular materials as claimed in claim 48, wherein said microparticle is enough big, thereby has avoided phagocytosis.

53. utilize radiation therapy to treat patient's method, comprising:

The a plurality of radiological predication fallout plot granules of patient that need radiation therapy, the particulate diameter of each radiological predication fallout plot in wherein said a plurality of radiological predication fallout plot granules is about 5 to about 200 microns scope, and right and wrong are biodegradable; And described microparticle comprises core, is positioned at least a connection carrier on the described core, and wherein said connection carrier comprises biocompatible polymer and be covalently bound at least a radiation treatment agent of described connection carrier,

Wherein said a plurality of radiological predication fallout plot granule offers described patient's radiation therapy.

54. method as claimed in claim 53, the wherein said parenteral that comprises gives.

55. method as claimed in claim 53 wherein saidly comprises intravenous injection.

56. method as claimed in claim 53 is wherein saidly carried out intravascular injection near being included in target location or target location.

57. method as claimed in claim 56, wherein said target location is a tumor.

58. method as claimed in claim 53, wherein said radiological predication fallout plot granule is fixed on the administration position.

59. method as claimed in claim 53 wherein saidly comprises that the arterial vascular system to supporting patient tumors carries out intravascular injection.

60. method as claimed in claim 53, wherein said patient is primary hepatocarcinoma or secondary liver cancer patient.

61. method as claimed in claim 53, wherein said patient suffers from hepatocarcinoma, rheumatoid arthritis, entity cancer, liver cancer, the brain cancer, breast carcinoma or ovarian cancer.

62. method as claimed in claim 53, wherein said patient suffers from renal cell carcinoma, hepatocarcinoma, sarcoma, head or neck cancer or central nerve neuroma.

63. method as claimed in claim 53, wherein said at least a radiation treatment agent comprise at least a in α-emission radionuclide, beta-emitting radionuclide or γ-emission radionuclide.

64. method as claimed in claim 53, wherein said at least a radiation treatment agent comprises α-emission radionuclide and beta-emitting radionuclide.

65. method as claimed in claim 53, wherein said at least a radiation treatment agent comprises beta-emitting radionuclide and γ-emission radionuclide.

66., further comprise and detect described γ-emission radionuclide, to determine the position of described a plurality of radiological predication fallout plot granules in the patient as the described method of claim 65.

67. Target organ or tumor to the patient are carried out imaging method, comprising:

Give the patient a plurality of radiological predication fallout plot granules in patient's target location, the particulate diameter of each radiological predication fallout plot in wherein said a plurality of radiological predication fallout plot granules is about 5 to about 200 micrometer ranges, and right and wrong are biodegradable; And described microparticle comprises core, is positioned at least a connection carrier on the described core, wherein said connection carrier comprises biocompatible polymer, with at least a radiation treatment agent that is covalently bound to described connection carrier, wherein said radiation treatment agent comprises γ-emission radionuclide;

Detect described a plurality of radiological predication fallout plot granule, wherein said detection provides the image of described Target organ or tumor.

68. as the described method of claim 67, wherein said detection is carried out at radiating life period.

69. as the described method of claim 67, wherein said detection is carried out after radiation.

70. as the described method of claim 67, wherein said at least a radiation treatment agent comprises at least a in α-emission radionuclide, β radiation radionuclide or the γ-emission radionuclide.

71. as the described method of claim 67, wherein said at least a radiation treatment agent comprises α-emission radionuclide and beta-emitting radionuclide.

72. as the described method of claim 67, wherein said at least a radiation treatment agent comprises beta-emitting radionuclide and γ-emission radionuclide.

73., further comprise and determine the position of described a plurality of radiological predication fallout plot granules in the patient as the described method of claim 67.

74. as the described method of claim 67, wherein said a plurality of microparticles are fixed on the target location.

75. as the described method of claim 74, wherein said target location is a tumor.

76. as the described method of claim 67, the diameter of each in wherein said a plurality of microparticles about 15 to about 35 microns scope.

77. have the method for cancer diagnosis among the patient of tumor in suspection, comprising:

In described patient's target location, give the patient a plurality of radiological predication fallout plot granules, the particulate diameter of each radiological predication fallout plot in wherein said a plurality of radiological predication fallout plot granules is about 5 to about 200 micrometer ranges, and right and wrong are biodegradable; And described microparticle comprises core, is positioned at least a connection carrier on the described core, wherein said connection carrier comprises biocompatible polymer, with at least a radiation treatment agent that is covalently bound to described connection carrier, wherein said radiation treatment agent comprises γ-emission radionuclide;

Detect described a plurality of radiological predication fallout plot granule; With

Determine by described detection whether described patient has tumor, wherein the detection that described tumor is done diagnoses out described patient to suffer from cancer.

78. as the described method of claim 77, wherein said cancer is hepatocarcinoma, entity cancer, the brain cancer, breast carcinoma or ovarian cancer.

79. as the described method of claim 77, wherein said tumor is renal cell carcinoma, hepatocarcinoma, sarcoma or central nerve neuroma.

80. as the described method of claim 77, wherein said at least a radiation treatment agent comprises at least a in α-emission radionuclide, beta-emitting radionuclide or γ-emission radionuclide.

81. as the described method of claim 77, wherein said at least a radiation treatment agent comprises α-emission radionuclide and beta-emitting radionuclide.

82. as the described method of claim 77, wherein said at least a radiation treatment agent comprises beta-emitting radionuclide and γ-emission radionuclide.

83. be used to prepare the test kit of the described granular materials of claim 48, wherein said test kit comprises:

The on-radiation core;

At least a connection carrier, it is used at least a radionuclide is attached to described granular core; With

The instrument that is used to prepare the guidance of described microparticulate therapeutic agents amount or is used to obtain described guidance.

84. as the described test kit of claim 83, wherein said test kit further comprises radionuclide.

85. as the described test kit of claim 83, wherein radionuclide separates with described test kit provides.

86. as the described test kit of claim 83, further comprise at least a component that is selected from following substances: pharmaceutically acceptable inert carrier, preparaton, adjuvant, active agent, water, saline, transfer ligand, Reducing agent, lyophilization aid, stabilization aid, solubilizing agent, antibacterial, cushion, x-ray contrast agent, acoustic contrast agent and metal medicine.

87., further comprise being selected from following at least a component: syringe, shielding device and imaging device as the described test kit of claim 83.

88., further comprise at least two kinds of chemically different on-radiation cores or at least two kinds of chemically different connection carrier as the described test kit of claim 83.

89. application rights requires 83 described test kits to come to prepare for the patient who needs the microparticle treatment method of microparticulate therapeutic agents amount, comprising:

By open patient's prescription, determine the type of required microparticle treatment and dosage and

By described guidance or obtain the instrument of described guidance, prepare described microparticulate therapeutic agents amount.

85. application rights requires 89 described test kits to come to prepare for the patient who needs the microparticle treatment method of microparticulate therapeutic agents amount, comprising:

By open patient's prescription, determine the type and the dosage of required microparticle treatment;

From the core that is contained in described test kit, select the type of on-radiation core;

From the junctional complex that is contained in described test kit, select the type of junctional complex;

The selective emission nucleic and