EP1735012A2 - Targeting of radioimagining and radiotherapy agents - Google Patents
Targeting of radioimagining and radiotherapy agentsInfo
- Publication number
- EP1735012A2 EP1735012A2 EP05778066A EP05778066A EP1735012A2 EP 1735012 A2 EP1735012 A2 EP 1735012A2 EP 05778066 A EP05778066 A EP 05778066A EP 05778066 A EP05778066 A EP 05778066A EP 1735012 A2 EP1735012 A2 EP 1735012A2
- Authority
- EP
- European Patent Office
- Prior art keywords
- polysaccharide
- composition
- boron
- gadolinium
- targeting
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
- A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
- A61K51/04—Organic compounds
- A61K51/06—Macromolecular compounds, carriers being organic macromolecular compounds, i.e. organic oligomeric, polymeric, dendrimeric molecules
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
- A61K47/61—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule the organic macromolecular compound being a polysaccharide or a derivative thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
- A61K49/08—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by the carrier
- A61K49/085—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by the carrier conjugated systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
- A61K49/08—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by the carrier
- A61K49/10—Organic compounds
- A61K49/12—Macromolecular compounds
- A61K49/124—Macromolecular compounds dendrimers, dendrons, hyperbranched compounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
- A61K49/08—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by the carrier
- A61K49/10—Organic compounds
- A61K49/12—Macromolecular compounds
- A61K49/126—Linear polymers, e.g. dextran, inulin, PEG
- A61K49/128—Linear polymers, e.g. dextran, inulin, PEG comprising multiple complex or complex-forming groups, being either part of the linear polymeric backbone or being pending groups covalently linked to the linear polymeric backbone
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
- A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
- A61K51/04—Organic compounds
- A61K51/06—Macromolecular compounds, carriers being organic macromolecular compounds, i.e. organic oligomeric, polymeric, dendrimeric molecules
- A61K51/065—Macromolecular compounds, carriers being organic macromolecular compounds, i.e. organic oligomeric, polymeric, dendrimeric molecules conjugates with carriers being macromolecules
Definitions
- the present invention pertains to body imaging through high energy radiation.
- the instant invention relates to compositions and methods used for targeting imaging radiation to affected tissue.
- An imaging agent is administered for visualizing body organs and tissues by scanning the agent's interactions with high-energy radiation.
- Computed axial tomography (CAT) and positron emission tomography (PET) are representative examples of radioimaging techniques currently in use in the clinical field.
- a radioimaging agent typically carries an isotope tag that provides information related to the organ's condition or the presence of a tumor.
- malignant cells must differentially bind the agent.
- Tumor cells have surface glyco-receptors that represent targeting structures well suited for radioimaging or radiotherapeutic agents.
- Radioisotopes suitable for use as radioimaging agents.
- the choice of radioisotope depends on factors including: isotope lifetime, modes of decay, decay energy, particle emission energies and neutron capture cross-sections.
- Radioisotopes are selected for particular radioimaging tasks based on the compatibility of the radioisotope properties with the imaging detector system, storage requirements and toxicity. Since the toxicity typically decreases and cellular uptake rates increase by bonding the radioisotope to a suitable carrier, one must further balance the synthetic chemistry necessary to bond a selected radioisotope to a carrier molecule against the imaging properties of the selected radioisotope.
- Previous efforts have involved bonding radioisotopes of fluorine, carbon and iodine to glucose or glucose-like molecules. Still other efforts have involved coating an inorganic core with carbohydrate molecules to facilitate cellular delivery.
- radioprotective agents functions to protect critical body tissues against low to moderate doses of ionizing radiation and the in situ generated free radicals associated with biological tissues being exposed to such radiation. Radioprotective agents are beneficially administered to patients receiving radioisotope and radiation treatments as well as to protect individuals entering radiation contaminated environments. Such a radioprotective agent serves antimutagenic and anticarcinogenic roles within tissues containing such an agent. Delivery of radioprotective agents has previously proven to be a limiting factor in their use.
- Boron neutron capture therapy is based on the nuclear reaction which occurs when a stable isotope, B-10 (present in 19.8% natural abundance), is irradiated with thermal neutrons to produce an alpha particle and a Li-7 nucleus. These particles have a path length of about one cell diameter, resulting in high linear energy transfer. Just a few of the short-range 1.7 MeV alpha particles produced in this nuclear reaction is sufficient to target the cell nucleus and destroy it.
- Nuclear reactors are the source of neutrons for BNCT. More recent advances with neutrons of intermediate energy (epithermal neutrons, 1-10,000 eV energy) have led to the consensus for its use in planned clinical trials in the US and Europe. Alam et al., J. Med. Chem., 32: 2326-30 (1989). Fast neutrons with a probable energy of 0.75 MeV are of little use in BNCT.
- the present invention relates to compositions and methods for targeting atoms, such as boron, to tumor cells, thus providing an enhanced boron neutron capture therapy (BNCT).
- BNCT is a binary system designed to deliver ionizing radiation to tumor cells by neutron irradiation of tumor-localized boron- 10 atoms.
- the cancer cells' extensive glyco-receptors (lectins) are targeted, for example, with a multivalent galactose branched polysaccharide wherein at least one carbohydrate, galactose, mannose or rhamnose specifically targets the tumor cells and delivers a carbohydrate chelated, for example, boron compound.
- the localized boron can then be used for imaging, scanning and/or therapeutic irradiation, thereby effecting treatment of the tumor in patients. It is therefore an object of the present invention to provide a composition and method for targeting therapeutically metal atoms or derivatives to tumor cells that overcomes the previous problems (described supra) and for delivering sufficient amounts for enhanced imaging for diagnostic, efficient radiotherapy, or chemotherapy of a metallic derivative.
- a branched ligand polysaccharide which chelates metal atoms, specifically boron, gadolinium or platinum atoms or therapeutic derivative and deliver them to tumor cells in a patient, comprising the step of administering to the patient a targeting composition comprising a chelate of (i) one or more branched ligand polysaccharide that target tumor cells' surface glyco-receptors, and (ii) one or more chelated metallic atoms.
- Administering to the patient a chelated composition and allowing them to localize at the tumor cells is within the scope of the present methods.
- an object of the present invention is the targeting of the tumor gly co- receptor enhances the internalization of the metallic polysaccharide complex into the cancer where the complex disintegrate to release cytotoxic metallic component , e.g. cisplatin.
- FIG.l is a schematic of a polysaccharide of the present invention
- FIG. 2 is a schematic of a boron chelated complex
- FIG. 3 is a schematic showing a metallic atom attached between two hydroxyl groups residing on the same polysaccharide or two molecules
- FIG. 4 is a schematic of different polysaccharides of the present invention
- FIG. 5 is a schematic showing boron chelation and the involvement of calcium.
- the present invention relates to improved compositions and methods used for targeting atoms, such as boron, to tumor cells, thus providing an enhanced boron neutron capture therapy (BNCT).
- BNCT is a binary system designed to deliver ionizing radiation to tumor cells by neutron irradiation of tumor-localized boron- 10 atoms.
- PS polysaccharide
- OS oligosaccharide
- EHS Eaglebreth-Holm Swarm
- DMEM Dulbecco's Modified Eagle's Minimal Essential Medium
- CMF-PBS Ca 2+ - and Mg 2+ -Free Phosphate-Buffered Saline, pH 7.2
- BSA Bovine Serum Albumin
- galUA galactopyranosyl uronic acid, also called galacturonic acid
- gal galactose
- man mannose
- glc glucose
- ara arabinose, rib, ribose
- lyx lyxose
- xyl xylose
- fru fructose
- psi psicose
- sor sorbose
- tag fru
- administering refers to parentereal including intravenous, subcutaneous, transdermal, transmucosal, intraperitoneal, and intramuscular or oral and topical
- Subject refers to an animal such as a mammal for example a human.
- Treatment of cancer refers to prognostic treatment of subjects at high risk of developing a cancer as well as subjects who have already developed a tumor.
- treatment may be applied to the reduction or prevention of abnormal cell proliferation, cell aggregation and cell dispersal (metastasis) to secondary sites.
- Cancer refers to any neoplastic disorder, including such cellular disorders as, for example, renal cell cancer, Kaposi's sarcoma, chronic leukemia, breast cancer, sarcoma, ovarian carcinoma, rectal cancer, throat cancer, melanoma, colon cancer, bladder cancer, mastocytoma, lung cancer, mammary adenocarcinoma, pharyngeal squamous cell carcinoma, and gastrointestinal or stomach cancer.
- Anti-cancer drugs chemicals that effectively hinder growth of proliferating cells including such molecules designated as cytotoxic, antimetabolite, anti- proliferation, anti-angiogenic, antitumour antibiotic, alkylating agent, mitotic inhibitor, endocrine anti-hormone, biological response modifier, tumor specific monoclonal antibody, apoptosis triggering agents and other molecules that effect cell viability.
- Delivery refers to partial or complete hydrolysis of the polysaccharide backbone occurring for example when the polysaccharide is treated chemically or enzymatically resulting in fragments of reduced size when compared with the original polysaccharide.
- Effective dose refers to a dose of an agent that improves the symptoms of the subject or the longevity of the subject suffering from or at high risk of suffering from cancer.
- saccharide refers to any simple carbohydrate including monosaccharides, monosaccharide derivatives, monosaccharide analogs, sugars, including those which form the individual units in an oligosaccharide or a polysaccharide.
- Methyde refers to polyhydroxy aldehyde (aldose) or polyhydroxyketone (ketose) and derivatives and analogs thereof.
- Oletaccharide refers to a linear or branched chain of monosaccharides that includes up to about 20 saccharide units linked via glycosidic bonds.
- Polysaccharide refers to polymers formed from about 10 to about 10,000 and more saccharide units linked to each other by hemiacetal or glycosidic bonds.
- the polysaccharide may be either a straight chain, singly branched, or multiply branched wherein each branch may have additional secondary branches, and the monosaccharides may be standard D- or L- cyclic sugars in the pyranose (6-membered ring) or furanose (5-membered ring) forms such as D-fructose and D-galactose, respectively, or they may be cyclic sugar derivatives, for example amino sugars such as D-glucosamine, deoxy sugars such as D-fucose or L-rhamnose, sugar phosphates such as D-ribose-5-phosphate, sugar acids such as D-galacturonic acid, or multi-derivatized sugars such as N-acetyl-D-glucosamine, N-acetylneuraminic
- Backbone means the major chain of a polysaccharide, or the chain originating from the major chain of a starting polysaccharide, having saccharide moieties sequentially linked by either or ⁇ glycosidic bonds.
- Esterification refers to the presence of methylesters or other ester groups at the carboxylic acid position of the uronic acid moieties of a saccharide.
- Substantially de-esterified means, for the purposes of this application, that the degree of esterification on the backbone of the polysaccharide is less than about
- Substantially lacks secondary branches of saccharides means that the polysaccharide backbone has less than about 1-2 secondary branches per repeating unit and no tertiary branches.
- Ligand refers to a molecule that binds to another molecule, used especially to refer to a small molecule that binds specifically to a larger molecule, e.g., an antigen binding to an antibody, a hormone or neurotransmitter binding to a receptor, a substrate or allosteric effector binding to enzyme or receptor.
- ligand the carbohydrates that specifically bind to glyco-receptors on tumor cells are defined as "ligand”.
- Multivalent ligand binding polysaccharide refers to a polysaccharide that poses more than two or more ligand structures which will facilitate multiple binding sites per one polymer. Due to the multivalent receptor sites on the tumor cells the multivalent ligand binding will enable a stronger and more specific interaction between the polysaccharide and the tumor.
- Bridge refers to a chemical structure which compose of 2 or more molecules that connected a specific agent (e.g. drug) to the delivery unit, for the purposes of this application a polysaccharide polymer.
- a specific agent e.g. drug
- the bridge is susaptable to degradation in the tumor micro-system.
- the Bridge could have peptide structure made of 2 to 6 amino-acids, e.g. glycyl peptide, oligosaccharide with 2-6 carbohydrate, example oligo ( ⁇ 1-4) glucosyl unit, any chemical with ester bonds or other bond that degraded in tumor cells.
- Glyco-receptors refers to membrane-associated structures on cells exposed to the exterior of the cells and specifically bind carbohydrate molecules. Glyco-receptors are refers to mainly protein associated with tumor cells and have been described in the literature as having high affinity to carbohydrate moieties, specifically the "galectins" which have high specific binding to galactose.
- cancer cells' extensive glyco receptors are targeted, for example, with a multivalent galactose branched polysaccharide wherein at least one carbohydrate, galactose, mannose or rhamnose specifically targets tumor cells, specifically delivered carbohydrate chelated boron compound.
- the localized boron may then be than use for imaging scanning or therapeutic irradiation, thereby effecting treatment of the tumor in patients.
- BNCT na 2 B 12 H n -SH
- the BNCT concept has been extended to other cancers, spurred on by the discovery of a number of tumor-localizing substances, including tumor-targeting monoclonal antibodies.
- tumor-targeting monoclonal antibodies For instance, boronated amino acids such as ju-borono- phenylalanine accumulated in melanoma cells.
- boronated monoclonal antibodies directed against cell surface antigens, such as CEA for BNCT of cancers has been demonstrated.
- Success with BNCT of cancer requires methods for localizing a high concentration of boron- 10 at tumor sites, while leaving non-target organs essentially boron-free.
- Dextran based radioimaging and radioprotective agents are characterized by slow cellular uptake and luck of targeting.
- U.S. Pat. No. 5,554,386 details the endocytosis of dextran therapeutics, the entire teaching of which is incorporated herein by reference.
- our ligand based polysaccharides bind to glyco-receptors located on tumor surfaces and may also induced endocytosis or faster diffusion rates into the tumor.
- Simple sugars such as methyl- ⁇ -D-lactoside and lacto-N-tetrose have been shown to inhibit metastasis of B16 melanoma cells, while D-galactose and arabinogalactose inhibited liver metastasis of L-1 sarcoma cells, as described by Beuth, J. et al, J. Cancer Res. Clin. Oncol., (1987), vol. 113, pp. 51-55, the entire teaching of which is incorporated herein by reference.
- the multivalent ligand polysaccharide have a capacity to deliver multiple units of same metal atom or derivative.
- a polysaccharide may have 1 to 100 or more conjugated effective metallic molecules and have up to 100 or more ligands linked to the polysaccharide backbone, each with a terminal saccharide comprising galactose, rhamnose, mannose, or derivatives thereof.
- Other suitable polysaccharides may have at least one side chain of saccharide ligand terminating with a saccharide modified by a feruloyl group.
- a multivalent-ligand-polysaccharide has a capacity to deliver multiple metallic atoms or derivatives of diversified functionality like Boron for diagnostic and Platinum for therapeutic.
- a polysaccharides may have up to 100 or more chelated linked metallic molecules and have up to 100 or more ligands linked to the polysaccharide backbone each with a terminal saccharide comprising, e.g., galactose, rhamnose, arabinose, or derivatives thereof.
- Other polysaccharides may have at least one side chain of saccharides ligand terminating with a saccharide modified by a feruloyl group.
- a boron compound is chelated to rhamnogalacturonate II. (See FIG. 1). All the RG-IIs contain the monosaccharides (apiose, 2-O-methyl-L-fucose, 2-O-methyl-D-xylose, Kdo, Dha, and aceric acid) that are diagnostic of RG-II.
- the glycosyl-linkages of the neutral and acidic sugars, including aceric acid, were determined simultaneously by GC-EIMS analysis of the methylated alditol acetates generated from per-O-methylated and carboxyl-reduced RG-II.
- RG-IIs Two of the RG-IIs contain boron most likely as a borate di-ester that crosslinks two molecules of RG-II together to form a dimmer. It is known in the art that a number of radioactive isotopes of gadolinium are available. These include alpha emitters as well as beta emitters. Some particularly useful isotopes comprise gadolinium 159, gadolinium 162 as well as gadolinium 150 and 151. Similar to a compound design by Willich, a German scientist, based on amino acid polymer complex for magnetic resonance angiography. (See, Vogtle, F. and Fischer, M., Angew. Chem. Int. Ed.
- Gadolinium ion complexes can be incorporated into chelating groups of branched polysaccharides providing multiple bonding sites along the polymer, allowing multiple MRI contrasting agent complexes to attach to one polymer.
- One branched polymer molecule can host up to 100 or more contrasting agents and hence attaining higher signal-to-noise ratio.
- the carbohydrate component targets the glyco-receptor providing a better contrast MRI picture.
- Conjugates Preparation, (Sebastien Gouin, et al) the multivalent ligand polysaccharide described above has the advantage of specific targeting to glyco- receptors.
- Combine imaging with radiolabeling further enhances the specificity of the therapy and radiotherapy for targeting radiation where a tumor is detected, thereby, reducing side effects associated with radiation therapy.
- the present invention uses multivalent ligand polysaccharide chelated to target platinum, boron, gadolinium or derivatives to tumor cells.
- the targeting composition comprises a chelate of at least one branched multivalent ligand polysaccharide which selectively binds to glyco-receptor associated with the tumor cells' surfaces.
- One embodiment of the invention is direct to methods for treating a patient afflicted with cancer.
- the method involve administering to a patient an effective amount of a targeting composition having (i) one or more polysaccharides, wherein said polysaccharide facilitates the targeting of a cancer cell, and (ii) one or more chelated metallic atoms; and irradiating said patient with sufficient energy so as to elaborate nuclear particles that are sufficient to destroy said cancer cell.
- a targeting composition having (i) one or more polysaccharides, wherein said polysaccharide facilitates the targeting of a cancer cell, and (ii) one or more chelated metallic atoms; and irradiating said patient with sufficient energy so as to elaborate nuclear particles that are sufficient to destroy said cancer cell.
- a branched ligand polysaccharide which chelates metal atoms, for example, boron, gadolinium or platinum atoms or therapeutic derivative and deliver them to tumor cells in a patient.
- the targeting is accomplished by using a polysaccharide that has affinity to glyco- receptors, for example, galectins, which are elaborated on the surface of cancer cells.
- Imaging technology used to obtained enhanced diagnostics of the tumors can be facilitated using the compositions and methods of the present invention.
- Any of the identified compounds of the present invention can be administered to a subject, including a human, by itself, or in pharmaceutical compositions where it is mixed with suitable carriers or excipients at doses therapeutically effective to prevent, treat or ameliorate a variety of disorders, including those characterized by that outlined herein.
- a therapeutically effective dose further refers to that amount of the compound sufficient result in the prevention or amelioration of symptoms associated with such disorders.
- the compounds of the present invention can be targeted to specific sites by direct injection into those sites.
- Compounds designed for use in the central nervous system should be able to cross the blood-brain barrier or be suitable for administration by localized injection.
- compositions suitable for use in the present invention include compositions wherein the active ingredients are contained in an effective amount to achieve its intended purpose. More specifically, a therapeutically effective amount means an amount effective to prevent development of or alleviate the existing symptoms and underlying pathology of the subject being treating. Determination of the effective amounts is well within the capability of those skilled in the art.
- the therapeutically effective dose can be estimated initially from cell culture assays.
- a dose can be formulated in animal models to achieve a circulating concentration range that includes the IC ⁇ (the dose where 50% of the cells show the desired effects) as determined in cell culture. Such information can be used to more accurately determine useful doses in humans.
- a therapeutically effective dose refers to that amount of the compound that results in the attenuation of symptoms or a prolongation of survival in a subject. Toxicity and therapeutic efficacy of such compounds can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LDgo (the dose lethal to 50% of a given population) and the ED 50 (the dose therapeutically effective in 50% of a given population). The dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio between LD ⁇ and ED ⁇ . Compounds which exhibit high therapeutic indices are preferred. The data obtained from these cell culture assays and animal studies can be used in formulating a range of dosage for use in human.
- the dosage of such compounds lies preferably within a range of circulating concentrations that include the ED 50 with little or no toxicity.
- the dosage can vary within this range depending upon the dosage form employed and the route of administration utilized.
- the exact formulation, route of administration and dosage can be chosen by the individual physician in view of a patient's condition. Dosage amount and interval can be adjusted individually to provide plasma levels of the active moiety which are sufficient to maintain the desired effects.
- the effective local concentration of the drug may not be related to plasma concentration.
- composition administered will, of course, be dependent on the subject being treated, on the subject's weight, the severity of the affliction, the manner of administration and the judgment of the prescribing physician.
- compositions of the present invention can be manufactured in a manner that is itself known, e.g., by means of conventional mixing, dissolving, granulating, levigating, emulsifying, encapsulating, entrapping or lyophilizing processes.
- Pharmaceutical compositions for use in accordance with the present invention thus can be formulated in conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen.
- the agents of the invention can be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hank's solution, Ringer's solution, or physiological saline buffer.
- physiologically compatible buffers such as Hank's solution, Ringer's solution, or physiological saline buffer.
- penetrants appropriate to the barriers to be permeated are used in the formulation. Such penetrants are generally known in the art.
- the compounds can be formulated readily by combining the active compounds with pharmaceutically acceptable carriers well known in the art.
- Such carriers enable the compounds of the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a subject to be treated.
- Pharmaceutical preparations for oral use can be obtained solid excipient, optionally grinding a resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores.
- Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and/or polyvinyl- pyrrolidone (PVP).
- disintegrating agents can be added, such as the cross- linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.
- Dragee cores are provided with suitable coatings.
- suitable coatings can be used, which can optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
- Dyestuffs or pigments can be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.
- compositions which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
- the push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
- the active compounds can be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols.
- stabilizers can be added. All formulations for oral administration should be in dosages suitable for such administration.
- compositions can take the form of tablets or lozenges formulated in conventional manner.
- the compounds for use according to the present invention are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant, e.g., dichlorodi- fluoromethane, trichlorofluoromethane, dichlorotetrafluoromethane, carbon dioxide or other suitable gas.
- a suitable propellant e.g., dichlorodi- fluoromethane, trichlorofluoromethane, dichlorotetrafluoromethane, carbon dioxide or other suitable gas.
- a pressurized aerosol the dosage unit can be determined by providing a valve to deliver a metered amount.
- Capsules and cartridges of e.g., gelatin for use in an inhaler or insufflator can be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.
- the compounds can be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion.
- Formulations for injection can be presented in unit dosage for, e.g., in ampoules or in multidose containers, with an added preservatives.
- the compositions can take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and can contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
- compositions for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Additionally, suspensions of the active compounds can be prepared as appropriate oily injection suspension. Suitable lipohilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes.
- Aqueous injection suspensions can contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran.
- the suspension can also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.
- the active ingredient can be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
- a suitable vehicle e.g., sterile pyrogen-free water
- the compounds can also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.
- the compounds can also be formulated as a depot preparation.
- Such long acting formulations can be administered by implantation (e.g., subcutaneously or intramuscularly) or by intramuscular injection.
- the compounds can be formulated with suitable polymeric or hydrophobic materials (e.g., as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, e.g., as a sparingly soluble salt.
- suitable polymeric or hydrophobic materials e.g., as an emulsion in an acceptable oil
- ion exchange resins e.g., as an emulsion in an acceptable oil
- sparingly soluble derivatives e.g., as a sparingly soluble salt.
- a pharmaceutical carrier for the hydrophobic compounds of the invention is a co- solvent system comprising benzyl alcohol, a non-polar surfactant, a water-miscible organic polymer, and an aqueous phase.
- benzyl alcohol a non-polar surfactant
- a water-miscible organic polymer a water-miscible organic polymer
- an aqueous phase a co-solvent system
- the proportions of a co-solvent system can be varied considerably without destroying its solubility and toxicity characteristics.
- identity of the co-solvent components can be varied.
- hydrophobic pharmaceutical compounds can be employed.
- Liposomes and emulsions are well known examples of delivery vehicles or carriers for hydrophobic drugs.
- Certain organic solvents such as dimethylsulfoxide also may be employed, although usually at the cost of greater toxicity.
- the compounds can be delivered using a sustained-release system, such as semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent.
- sustained-release materials have been established and are well known to those skilled in the art. Sustained-release capsules can, depending on their chemical nature, release the compounds for a few weeks up to over 100 days. Depending on the chemical nature and the biological stability of the therapeutic reagent, additional strategies for protein stabilization can be employed.
- compositions also can comprise suitable solid or gel phase carriers or excipients.
- suitable solid or gel phase carriers or excipients include, but are not limited to, calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols.
- compositions of the invention can be provided as salts with pharmaceutically compatible counterions.
- Pharmaceutically compatible salts can be formed with many acids, including but not limited to hydrochloric, sulfuric, acetic, lactic, tartaric, malic, succinic, etc. Salts tend to be more soluble in aqueous or other protonic solvents that are the corresponding free base forms.
- Suitable routes of administration can, e.g., include oral, rectal, transmucosal, transdermal, or intestinal administration; parenteral delivery, including intramuscular, subcutaneous, intramedullary injections, as well as intrathecal, direct intraventricular, intravenous, intraperitoneal, intranasal, or intraocular injections.
- one can administer the compound in a local rather than systemic manner e.g., via injection of the compound directly into an affected area, often in a depot or sustained release formulation.
- one can administer the compound in a targeted drug delivery system e.g., in a liposome coated with an antibody specific for affected cells.
- the liposomes will be targeted to and taken up selectively by the cells.
- compositions can, if desired, be presented in a pack or dispenser device which can contain one or more unit dosage forms containing the active ingredient.
- the pack can, e.g., comprise metal or plastic foil, such as a blister pack.
- the pack or dispenser device can be accompanied by instruction for administration.
- Compositions comprising a compound of the invention formulated in a compatible pharmaceutical carrier can also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition. Suitable conditions indicated on the label can include treatment of a disease such as described herein.
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Abstract
Disclosed herein are compositions and methods for targeting atoms, such as boron to tumor cells, thus providing an enhanced boron neutron capture therapy (BNCT).
Description
TARGETING OF RADIOIMAGING AND RADIOTHERAPY AGENTS
RELATED APPLICATIONS This application claims the benefit of and priority to US Provisional application 60/561,769, filed April 13, 2004.
FIELD OF THE INVENTION The present invention pertains to body imaging through high energy radiation. In particular, the instant invention relates to compositions and methods used for targeting imaging radiation to affected tissue.
BACKGROUND OF THE INVENTION
An imaging agent is administered for visualizing body organs and tissues by scanning the agent's interactions with high-energy radiation. Computed axial tomography (CAT) and positron emission tomography (PET) are representative examples of radioimaging techniques currently in use in the clinical field. A radioimaging agent typically carries an isotope tag that provides information related to the organ's condition or the presence of a tumor. For a radioimaging agent to be effective in visualizing tumors, malignant cells must differentially bind the agent. Tumor cells have surface glyco-receptors that represent targeting structures well suited for radioimaging or radiotherapeutic agents.
There are a number of radioisotopes suitable for use as radioimaging agents. The choice of radioisotope depends on factors including: isotope lifetime, modes of decay, decay energy, particle emission energies and neutron capture cross-sections. Radioisotopes are selected for particular radioimaging tasks based on the compatibility of the radioisotope properties with the imaging detector system, storage requirements and toxicity. Since the toxicity typically decreases and cellular uptake rates increase
by bonding the radioisotope to a suitable carrier, one must further balance the synthetic chemistry necessary to bond a selected radioisotope to a carrier molecule against the imaging properties of the selected radioisotope. Previous efforts have involved bonding radioisotopes of fluorine, carbon and iodine to glucose or glucose-like molecules. Still other efforts have involved coating an inorganic core with carbohydrate molecules to facilitate cellular delivery.
There is also an important need for radioprotective agents. A radioprotective agent functions to protect critical body tissues against low to moderate doses of ionizing radiation and the in situ generated free radicals associated with biological tissues being exposed to such radiation. Radioprotective agents are beneficially administered to patients receiving radioisotope and radiation treatments as well as to protect individuals entering radiation contaminated environments. Such a radioprotective agent serves antimutagenic and anticarcinogenic roles within tissues containing such an agent. Delivery of radioprotective agents has previously proven to be a limiting factor in their use.
Boron neutron capture therapy (BNCT) is based on the nuclear reaction which occurs when a stable isotope, B-10 (present in 19.8% natural abundance), is irradiated with thermal neutrons to produce an alpha particle and a Li-7 nucleus. These particles have a path length of about one cell diameter, resulting in high linear energy transfer. Just a few of the short-range 1.7 MeV alpha particles produced in this nuclear reaction is sufficient to target the cell nucleus and destroy it. (See, Barth et al., Cancer, 70: 2995-3007 (1992).) Since the 10B(n, α) 7Li reaction will occur, and thereby produce significant biological effect, only when there is a sufficient number of thermal neutrons and a critical amount of B-10 localized around or within the malignant cell, the radiation produced is localized. The neutron capture cross section of B-10 far exceeds that of nitrogen and hydrogen found in tissues, which also can undergo capture reactions, (relative numbers: 1 for N-14, 5.3 for H-l, and 11560 for B-10), so that once a high concentration differential of B-10 is achieved between normal and malignant
cells, only the latter will be affected upon neutron irradiation. This is the scientific basis for boron neutron capture therapy. Barth et al, supra; Barth et al. Cancer Res., 50: 1061-70 (1990); Perks et al., Brit. J. Radiol., 61: 1115-26 (1988). Nuclear reactors are the source of neutrons for BNCT. More recent advances with neutrons of intermediate energy (epithermal neutrons, 1-10,000 eV energy) have led to the consensus for its use in planned clinical trials in the US and Europe. Alam et al., J. Med. Chem., 32: 2326-30 (1989). Fast neutrons with a probable energy of 0.75 MeV are of little use in BNCT.
Original calculations estimated that a boron concentration of 35-50 μg per gram of tumor, or 109 B-10 atoms per tumor cell, would be necessary to sustain a cell-killing nuclear reaction with thermal neutron fluences of 1012"13 n.cm"2. (see, Fairchild et al, Int. J. Radiat. Oncol. Biol. Phys., 11: 831 (1985).) Thus, there is need for a method of targeting boron atoms to tumor cells that is able to deliver a large amount of boron atoms to tumor sites, while leaving noncancerous sites relatively boron-free.
BRIEF SUMMARY OF THE INVENTION
The present invention relates to compositions and methods for targeting atoms, such as boron, to tumor cells, thus providing an enhanced boron neutron capture therapy (BNCT). BNCT is a binary system designed to deliver ionizing radiation to tumor cells by neutron irradiation of tumor-localized boron- 10 atoms. In the present invention, the cancer cells' extensive glyco-receptors (lectins) are targeted, for example, with a multivalent galactose branched polysaccharide wherein at least one carbohydrate, galactose, mannose or rhamnose specifically targets the tumor cells and delivers a carbohydrate chelated, for example, boron compound. The localized boron can then be used for imaging, scanning and/or therapeutic irradiation, thereby effecting treatment of the tumor in patients.
It is therefore an object of the present invention to provide a composition and method for targeting therapeutically metal atoms or derivatives to tumor cells that overcomes the previous problems (described supra) and for delivering sufficient amounts for enhanced imaging for diagnostic, efficient radiotherapy, or chemotherapy of a metallic derivative.
In accomplishing these and other objects of the invention, a branched ligand polysaccharide is provided, which chelates metal atoms, specifically boron, gadolinium or platinum atoms or therapeutic derivative and deliver them to tumor cells in a patient, comprising the step of administering to the patient a targeting composition comprising a chelate of (i) one or more branched ligand polysaccharide that target tumor cells' surface glyco-receptors, and (ii) one or more chelated metallic atoms.
Metallic atom that are of therapeutic importance like boron, gadolinium, platinum atoms or their derivatives are within the scope of the current invention.
Administering to the patient a chelated composition and allowing them to localize at the tumor cells is within the scope of the present methods.
Further using imaging technology to obtained enhanced diagnostics of the tumors using a metallic atom, e.g. gadolinium, is within the scope of the present invention.
Further using irradiation technology which focuses on the metallic compound localized at the tumor cells, thereby effecting BNCT of the tumor cells, e.g. boron, is within the scope of the present method.
Further, an object of the present invention is the targeting of the tumor gly co- receptor enhances the internalization of the metallic polysaccharide complex into the cancer where the complex disintegrate to release cytotoxic metallic component , e.g. cisplatin.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG.l is a schematic of a polysaccharide of the present invention; FIG. 2 is a schematic of a boron chelated complex; FIG. 3 is a schematic showing a metallic atom attached between two hydroxyl groups residing on the same polysaccharide or two molecules; FIG. 4 is a schematic of different polysaccharides of the present invention; and FIG. 5 is a schematic showing boron chelation and the involvement of calcium. DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to improved compositions and methods used for targeting atoms, such as boron, to tumor cells, thus providing an enhanced boron neutron capture therapy (BNCT). BNCT is a binary system designed to deliver ionizing radiation to tumor cells by neutron irradiation of tumor-localized boron- 10 atoms.
Abbreviations used herein are: PS, polysaccharide; OS, oligosaccharide; EHS, Eaglebreth-Holm Swarm; DMEM, Dulbecco's Modified Eagle's Minimal Essential Medium; CMF-PBS, Ca2+- and Mg2+-Free Phosphate-Buffered Saline, pH 7.2; BSA, Bovine Serum Albumin; galUA, galactopyranosyl uronic acid, also called galacturonic acid; and gal, galactose; man, mannose; glc, glucose; all, allose; alt, altrose; ido, idose; tal, talose; gul, gulose; and ara, arabinose, rib, ribose; lyx, lyxose; xyl, xylose; and fru,
fructose; psi, psicose; sor, sorbose; tag, tagatose; and rha, rhamnose; fuc, fucose; quin, quinovose; 2-d-rib, 2-deoxy-ribose. As used in this description and the accompanying claims, the following terms shall have the meanings indicated, unless the context otherwise require:
"Administration" refers to parentereal including intravenous, subcutaneous, transdermal, transmucosal, intraperitoneal, and intramuscular or oral and topical
"Subject" refers to an animal such as a mammal for example a human.
"Treatment of cancer" refers to prognostic treatment of subjects at high risk of developing a cancer as well as subjects who have already developed a tumor. The term "treatment" may be applied to the reduction or prevention of abnormal cell proliferation, cell aggregation and cell dispersal (metastasis) to secondary sites.
"Cancer" refers to any neoplastic disorder, including such cellular disorders as, for example, renal cell cancer, Kaposi's sarcoma, chronic leukemia, breast cancer, sarcoma, ovarian carcinoma, rectal cancer, throat cancer, melanoma, colon cancer, bladder cancer, mastocytoma, lung cancer, mammary adenocarcinoma, pharyngeal squamous cell carcinoma, and gastrointestinal or stomach cancer.
"Anti-cancer drugs" chemicals that effectively hinder growth of proliferating cells including such molecules designated as cytotoxic, antimetabolite, anti- proliferation, anti-angiogenic, antitumour antibiotic, alkylating agent, mitotic inhibitor, endocrine anti-hormone, biological response modifier, tumor specific monoclonal antibody, apoptosis triggering agents and other molecules that effect cell viability.
"Depolymerization" refers to partial or complete hydrolysis of the polysaccharide backbone occurring for example when the polysaccharide is treated chemically or enzymatically resulting in fragments of reduced size when compared with the original polysaccharide.
"Effective dose" refers to a dose of an agent that improves the symptoms of the subject or the longevity of the subject suffering from or at high risk of suffering from cancer.
"Saccharide" refers to any simple carbohydrate including monosaccharides, monosaccharide derivatives, monosaccharide analogs, sugars, including those which form the individual units in an oligosaccharide or a polysaccharide.
"Monosaccharide" refers to polyhydroxy aldehyde (aldose) or polyhydroxyketone (ketose) and derivatives and analogs thereof.
"Oligosaccharide" refers to a linear or branched chain of monosaccharides that includes up to about 20 saccharide units linked via glycosidic bonds.
"Polysaccharide" refers to polymers formed from about 10 to about 10,000 and more saccharide units linked to each other by hemiacetal or glycosidic bonds. The polysaccharide may be either a straight chain, singly branched, or multiply branched wherein each branch may have additional secondary branches, and the monosaccharides may be standard D- or L- cyclic sugars in the pyranose (6-membered ring) or furanose (5-membered ring) forms such as D-fructose and D-galactose, respectively, or they may be cyclic sugar derivatives, for example amino sugars such as D-glucosamine, deoxy sugars such as D-fucose or L-rhamnose, sugar phosphates such as D-ribose-5-phosphate, sugar acids such as D-galacturonic acid, or multi-derivatized
sugars such as N-acetyl-D-glucosamine, N-acetylneuraminic acid (sialic acid), or N- sulfato-D-glucosamine.
"Backbone" means the major chain of a polysaccharide, or the chain originating from the major chain of a starting polysaccharide, having saccharide moieties sequentially linked by either or β glycosidic bonds.
"Esterification" refers to the presence of methylesters or other ester groups at the carboxylic acid position of the uronic acid moieties of a saccharide.
"Substantially de-esterified" means, for the purposes of this application, that the degree of esterification on the backbone of the polysaccharide is less than about
5%.
"Substantially lacks secondary branches of saccharides" means that the polysaccharide backbone has less than about 1-2 secondary branches per repeating unit and no tertiary branches.
"Ligand" refers to a molecule that binds to another molecule, used especially to refer to a small molecule that binds specifically to a larger molecule, e.g., an antigen binding to an antibody, a hormone or neurotransmitter binding to a receptor, a substrate or allosteric effector binding to enzyme or receptor. For the purposes of this application, the carbohydrates that specifically bind to glyco-receptors on tumor cells are defined as "ligand".
"Multivalent ligand binding polysaccharide" refers to a polysaccharide that poses more than two or more ligand structures which will facilitate multiple binding sites per one polymer. Due to the multivalent receptor sites on the tumor cells the
multivalent ligand binding will enable a stronger and more specific interaction between the polysaccharide and the tumor.
"Bridge" refers to a chemical structure which compose of 2 or more molecules that connected a specific agent (e.g. drug) to the delivery unit, for the purposes of this application a polysaccharide polymer. For the purposes of this application the bridge is susaptable to degradation in the tumor micro-system. The Bridge could have peptide structure made of 2 to 6 amino-acids, e.g. glycyl peptide, oligosaccharide with 2-6 carbohydrate, example oligo (α 1-4) glucosyl unit, any chemical with ester bonds or other bond that degraded in tumor cells.
"Glyco-receptors" refers to membrane-associated structures on cells exposed to the exterior of the cells and specifically bind carbohydrate molecules. Glyco-receptors are refers to mainly protein associated with tumor cells and have been described in the literature as having high affinity to carbohydrate moieties, specifically the "galectins" which have high specific binding to galactose.
In the present invention, cancer cells' extensive glyco receptors (lectins) are targeted, for example, with a multivalent galactose branched polysaccharide wherein at least one carbohydrate, galactose, mannose or rhamnose specifically targets tumor cells, specifically delivered carbohydrate chelated boron compound. The localized boron may then be than use for imaging scanning or therapeutic irradiation, thereby effecting treatment of the tumor in patients.
Historically, BNCT was first employed for the treatment of glioblastoma (a fatal form of brain tumor) and other brain tumors at a time when tumor specific substances were almost unknown. (See, Hatanaka et al., in BORON NEUTRON CAPTURE THERAPY FOR TUMORS, pp.349-78 (Nishimura Co., 1986), the entire teaching of which is incorporated herein by reference.) One of the first boronated
compounds employed, a sulfhydryl-containing boron substance called sodium borocaptate or BSH (Na2B12Hn-SH), crosses the blood-brain barrier to localize in brain, and this has been the anatomical basis for neutron capture therapy of brain tumors. Clinical trials have been carried out, or are scheduled, for the treatment of gliomas in Japan, the US and Europe. (See, Barth et al, Cancer, supra, the entire teaching of which is incorporated herein by reference.) Problems with previous inorganic boron therapy methods was that the boron reached both targeted and non- target areas. Accordingly, when the boron was irradiated, healthy cells as well as cancerous cells were destroyed.
The BNCT concept has been extended to other cancers, spurred on by the discovery of a number of tumor-localizing substances, including tumor-targeting monoclonal antibodies. For instance, boronated amino acids such as ju-borono- phenylalanine accumulated in melanoma cells. The potential of using boronated monoclonal antibodies directed against cell surface antigens, such as CEA, for BNCT of cancers has been demonstrated. (See: Ichihashi et al., J. Invest. Dermatol, 78: 215- 18 (1982); Goldenberg et al, P.N.A.S., USA, 81:560-63 (1984); Mizusawa et al. P.N.A.S., USA, 79: 3011-14 (1982); Barth et al, Hybridoma, 5(supp. 1): 543-5540 (1986); Ranadive et al. Nuci. Med. Biol., 20: 663-68 (1993).) However, heavily boronated antibodies failed to target tumor in vivo in animal models. (See, Alam et al, supra; Barth et al, Bioconjugate Chem., 5: 58-66 (1994), the entire teachings of which are incorporated herein by reference. )
Success with BNCT of cancer requires methods for localizing a high concentration of boron- 10 at tumor sites, while leaving non-target organs essentially boron-free.
Dextran based radioimaging and radioprotective agents are characterized by slow cellular uptake and luck of targeting. For example, U.S. Pat. No. 5,554,386
details the endocytosis of dextran therapeutics, the entire teaching of which is incorporated herein by reference. In contrast our ligand based polysaccharides, bind to glyco-receptors located on tumor surfaces and may also induced endocytosis or faster diffusion rates into the tumor.
It is generally accepted that many stages of the metastatic cascade involve cellular interactions mediated by cell surface components such as carbohydrate-binding proteins, which include galactoside binding lectins (galectins) as described by Raz, A. et al., (1987) Cancer Metastasis Rev., vol. 6, p. 433; and Gabius, H.-J., Biochimica et Biophysica Acta, (1991), vol. 1071 pp 1-18, the entire teachings of which are incorporated herein by reference. Treatment of B16 melanoma and uv-2237 fibrosarcoma cells in vitro with anti-galectin monoclonal antibodies prior to their intravenous (i.v.) injection into the tail vein of syngenic mice resulted in a marked inhibition of tumor lung colony development, as described by Meromsky, L. et al, Cancer Research, (1986), vol. 46, pp. 5270-5275, the entire teaching of which is incorporated herein by reference. Transfection of low metastatic, low galectin-3 expressing uv-2237-cll5 fibrosarcoma cells with galectin-3 cDNA resulted in an increase of the metastatic phenotype of the transfected cells, as described by Raz, A. et al., Int J. Cancer, (1990), vol. 46, pp. 871-877, the entire teaching of which is incorporated herein by reference. Furthermore, a correlation has been established between the level of galectin-3 expression in human papillary thyroid carcinoma and tumor stage of human colorectal and gastric carcinomas, as described by Chiariotti, L. et al, Oncogene, (1992), vol. 7, pp. 2507-2511; Irimura, T. et al, Cancer Res., (1991), vol. 51, pp. 387-393; Lotan, R., et al, Int. J. Cancer, (1994), vol. 56, pp. 1-20; Lotz, M. et al, Proc. Natl. Acad. Sci., USA, (1993), vol. 90, pp. 3466-3470, the entire teachings of which are incorporated herein by reference.
Simple sugars such as methyl-α-D-lactoside and lacto-N-tetrose have been shown to inhibit metastasis of B16 melanoma cells, while D-galactose and arabinogalactose inhibited liver metastasis of L-1 sarcoma cells, as described by Beuth,
J. et al, J. Cancer Res. Clin. Oncol., (1987), vol. 113, pp. 51-55, the entire teaching of which is incorporated herein by reference.
In one embodiment of the invention, the multivalent ligand polysaccharide have a capacity to deliver multiple units of same metal atom or derivative. In one aspect, a polysaccharide may have 1 to 100 or more conjugated effective metallic molecules and have up to 100 or more ligands linked to the polysaccharide backbone, each with a terminal saccharide comprising galactose, rhamnose, mannose, or derivatives thereof. Other suitable polysaccharides may have at least one side chain of saccharide ligand terminating with a saccharide modified by a feruloyl group.
In another embodiment of the invention, a multivalent-ligand-polysaccharide has a capacity to deliver multiple metallic atoms or derivatives of diversified functionality like Boron for diagnostic and Platinum for therapeutic. In one aspect, a polysaccharides may have up to 100 or more chelated linked metallic molecules and have up to 100 or more ligands linked to the polysaccharide backbone each with a terminal saccharide comprising, e.g., galactose, rhamnose, arabinose, or derivatives thereof. Other polysaccharides may have at least one side chain of saccharides ligand terminating with a saccharide modified by a feruloyl group.
In one embodiment of the present invention, a boron compound is chelated to rhamnogalacturonate II. (See FIG. 1). All the RG-IIs contain the monosaccharides (apiose, 2-O-methyl-L-fucose, 2-O-methyl-D-xylose, Kdo, Dha, and aceric acid) that are diagnostic of RG-II. The glycosyl-linkages of the neutral and acidic sugars, including aceric acid, were determined simultaneously by GC-EIMS analysis of the methylated alditol acetates generated from per-O-methylated and carboxyl-reduced RG-II. Two of the RG-IIs contain boron most likely as a borate di-ester that crosslinks two molecules of RG-II together to form a dimmer.
It is known in the art that a number of radioactive isotopes of gadolinium are available. These include alpha emitters as well as beta emitters. Some particularly useful isotopes comprise gadolinium 159, gadolinium 162 as well as gadolinium 150 and 151. Similar to a compound design by Willich, a German scientist, based on amino acid polymer complex for magnetic resonance angiography. (See, Vogtle, F. and Fischer, M., Angew. Chem. Int. Ed. 1999, V38, 884-905, the entire teaching of which is incorporated herein by reference.) Gadolinium ion complexes can be incorporated into chelating groups of branched polysaccharides providing multiple bonding sites along the polymer, allowing multiple MRI contrasting agent complexes to attach to one polymer. One branched polymer molecule can host up to 100 or more contrasting agents and hence attaining higher signal-to-noise ratio. Further, the carbohydrate component targets the glyco-receptor providing a better contrast MRI picture.
Similar to Gadolinium Diethylenetriaminepentaacetic Acid Hyaluronan
Conjugates: Preparation, (Sebastien Gouin, et al) the multivalent ligand polysaccharide described above has the advantage of specific targeting to glyco- receptors.
Combine imaging with radiolabeling further enhances the specificity of the therapy and radiotherapy for targeting radiation where a tumor is detected, thereby, reducing side effects associated with radiation therapy.
As mentioned above, the present invention uses multivalent ligand polysaccharide chelated to target platinum, boron, gadolinium or derivatives to tumor cells. The targeting composition comprises a chelate of at least one branched multivalent ligand polysaccharide which selectively binds to glyco-receptor associated with the tumor cells' surfaces.
One embodiment of the invention is direct to methods for treating a patient afflicted with cancer. The method involve administering to a patient an effective amount of a targeting composition having (i) one or more polysaccharides, wherein said polysaccharide facilitates the targeting of a cancer cell, and (ii) one or more chelated metallic atoms; and irradiating said patient with sufficient energy so as to elaborate nuclear particles that are sufficient to destroy said cancer cell.
In accomplishing these methods, a branched ligand polysaccharide is employed, which chelates metal atoms, for example, boron, gadolinium or platinum atoms or therapeutic derivative and deliver them to tumor cells in a patient. The targeting is accomplished by using a polysaccharide that has affinity to glyco- receptors, for example, galectins, which are elaborated on the surface of cancer cells.
Imaging technology used to obtained enhanced diagnostics of the tumors can be facilitated using the compositions and methods of the present invention.
Any of the identified compounds of the present invention can be administered to a subject, including a human, by itself, or in pharmaceutical compositions where it is mixed with suitable carriers or excipients at doses therapeutically effective to prevent, treat or ameliorate a variety of disorders, including those characterized by that outlined herein. A therapeutically effective dose further refers to that amount of the compound sufficient result in the prevention or amelioration of symptoms associated with such disorders. Techniques for formulation and administration of the compounds of the instant invention may be found in Goodman and Gilman's The Pharmacological Basis of Therapeutics, Pergamon Press, latest edition.
The compounds of the present invention can be targeted to specific sites by direct injection into those sites. Compounds designed for use in the central nervous system
should be able to cross the blood-brain barrier or be suitable for administration by localized injection.
Pharmaceutical compositions suitable for use in the present invention include compositions wherein the active ingredients are contained in an effective amount to achieve its intended purpose. More specifically, a therapeutically effective amount means an amount effective to prevent development of or alleviate the existing symptoms and underlying pathology of the subject being treating. Determination of the effective amounts is well within the capability of those skilled in the art.
For any compound used in the methods of the present invention, the therapeutically effective dose can be estimated initially from cell culture assays. For example, a dose can be formulated in animal models to achieve a circulating concentration range that includes the IC^ (the dose where 50% of the cells show the desired effects) as determined in cell culture. Such information can be used to more accurately determine useful doses in humans.
A therapeutically effective dose refers to that amount of the compound that results in the attenuation of symptoms or a prolongation of survival in a subject. Toxicity and therapeutic efficacy of such compounds can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LDgo (the dose lethal to 50% of a given population) and the ED50 (the dose therapeutically effective in 50% of a given population). The dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio between LD^ and ED^. Compounds which exhibit high therapeutic indices are preferred. The data obtained from these cell culture assays and animal studies can be used in formulating a range of dosage for use in human. The dosage of such compounds lies preferably within a range of circulating concentrations that include the ED50 with little or no toxicity. The dosage can vary within this range depending upon the dosage form employed and the route of administration utilized. The exact formulation, route of administration and dosage can be chosen by the individual physician in view of a patient's condition. Dosage amount and
interval can be adjusted individually to provide plasma levels of the active moiety which are sufficient to maintain the desired effects.
In case of local administration or selective uptake, the effective local concentration of the drug may not be related to plasma concentration.
The amount of composition administered will, of course, be dependent on the subject being treated, on the subject's weight, the severity of the affliction, the manner of administration and the judgment of the prescribing physician.
The pharmaceutical compositions of the present invention can be manufactured in a manner that is itself known, e.g., by means of conventional mixing, dissolving, granulating, levigating, emulsifying, encapsulating, entrapping or lyophilizing processes. Pharmaceutical compositions for use in accordance with the present invention thus can be formulated in conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen.
For injection, the agents of the invention can be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hank's solution, Ringer's solution, or physiological saline buffer. For transmucosal administration, penetrants appropriate to the barriers to be permeated are used in the formulation. Such penetrants are generally known in the art.
For oral administration, the compounds can be formulated readily by combining the active compounds with pharmaceutically acceptable carriers well known in the art. Such carriers enable the compounds of the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a subject to be treated. Pharmaceutical preparations for oral use can be
obtained solid excipient, optionally grinding a resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and/or polyvinyl- pyrrolidone (PVP). If desired, disintegrating agents can be added, such as the cross- linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.
Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions can be used, which can optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments can be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.
Pharmaceutical preparations which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds can be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers can be added. All formulations for oral administration should be in dosages suitable for such administration.
For buccal administration, the compositions can take the form of tablets or lozenges formulated in conventional manner.
For administration by inhalation, the compounds for use according to the present invention are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant, e.g., dichlorodi- fluoromethane, trichlorofluoromethane, dichlorotetrafluoromethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol the dosage unit can be determined by providing a valve to deliver a metered amount. Capsules and cartridges of e.g., gelatin for use in an inhaler or insufflator can be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch. The compounds can be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion. Formulations for injection can be presented in unit dosage for, e.g., in ampoules or in multidose containers, with an added preservatives. The compositions can take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and can contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Additionally, suspensions of the active compounds can be prepared as appropriate oily injection suspension. Suitable lipohilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions can contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension can also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.
Alternatively, the active ingredient can be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
The compounds can also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides. In addition to the formulations previously described, the compounds can also be formulated as a depot preparation. Such long acting formulations can be administered by implantation (e.g., subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds can be formulated with suitable polymeric or hydrophobic materials (e.g., as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, e.g., as a sparingly soluble salt.
A pharmaceutical carrier for the hydrophobic compounds of the invention is a co- solvent system comprising benzyl alcohol, a non-polar surfactant, a water-miscible organic polymer, and an aqueous phase. Naturally, the proportions of a co-solvent system can be varied considerably without destroying its solubility and toxicity characteristics. Furthermore, the identity of the co-solvent components can be varied.
Altenatively, other delivery systems for hydrophobic pharmaceutical compounds can be employed. Liposomes and emulsions are well known examples of delivery vehicles or carriers for hydrophobic drugs. Certain organic solvents such as dimethylsulfoxide also may be employed, although usually at the cost of greater toxicity. Additionally, the compounds can be delivered using a sustained-release system, such as semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent. Various of sustained-release materials have been established and are well known to those skilled in the art. Sustained-release capsules can, depending on their chemical nature, release the compounds for a few weeks up to over 100 days. Depending on the chemical nature and the biological stability of the therapeutic reagent, additional strategies for protein stabilization can be employed. The pharmaceutical compositions also can comprise suitable solid or gel phase carriers or excipients. Examples of such carriers or excipients include, but are not limited
to, calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols.
Many of the compounds of the invention can be provided as salts with pharmaceutically compatible counterions. Pharmaceutically compatible salts can be formed with many acids, including but not limited to hydrochloric, sulfuric, acetic, lactic, tartaric, malic, succinic, etc. Salts tend to be more soluble in aqueous or other protonic solvents that are the corresponding free base forms. Suitable routes of administration can, e.g., include oral, rectal, transmucosal, transdermal, or intestinal administration; parenteral delivery, including intramuscular, subcutaneous, intramedullary injections, as well as intrathecal, direct intraventricular, intravenous, intraperitoneal, intranasal, or intraocular injections. Alternatively, one can administer the compound in a local rather than systemic manner, e.g., via injection of the compound directly into an affected area, often in a depot or sustained release formulation.
Furthermore, one can administer the compound in a targeted drug delivery system, e.g., in a liposome coated with an antibody specific for affected cells. The liposomes will be targeted to and taken up selectively by the cells.
The compositions can, if desired, be presented in a pack or dispenser device which can contain one or more unit dosage forms containing the active ingredient. The pack can, e.g., comprise metal or plastic foil, such as a blister pack. The pack or dispenser device can be accompanied by instruction for administration. Compositions comprising a compound of the invention formulated in a compatible pharmaceutical carrier can also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition. Suitable conditions indicated on the label can include treatment of a disease such as described herein.
Claims
1. A composition used to target one or more atoms, comprising a metallic atom and a polysaccharide, wherein said polysaccharide has affinity for a glyco-receptor.
2. The composition of claim 1, wherein said metallic atom is selected from group consisting of boron, gadolinium, platinum or a combination thereof.
3. The composition of claim 2, wherein said metallic atom is boron.
4. The composition of claim 3, wherein said boron atom is boron-10.
5. The composition of claim 2, wherein said gadolinium is selected from the group consisting of gadolinium 150, gadolinium 151, gadolinium 159, and gadolinium 160.
6. The composition of claim 1, wherein said polysaccharide is selected from the group consisting of galactose, rhamnose, mannose or a combination thereof.
7. The composition of claim 1, wherein said polysaccharide is rhamnogalacturonate II.
8. The composition of claim 1, wherein said polysaccharide is branched.
9. The composition of claim 8, wherein said branched polysaccharide chelates one or more metallic atoms.
10. The composition of claim 9, wherein said polysaccharide chelates from about 1 to about 100 metallic atoms.
11. The composition of claim 1, wherein said glyco-receptor is a galectin receptor.
12. The composition of claim 1, wherein said glyco-receptor is elaborated on a tumor cell.
13. A method of treating a cancer patient, comprising: administering to said patient an effective amount of a targeting composition having (i) one or more polysaccharides, wherein said polysaccharide facilitates the targeting of a cancer cell, and (ii) one or more chelated metallic atoms; and irradiating said patient with sufficient energy so as to elaborate nuclear particles that are sufficient to destroy said cancer cell.
14. The method of claim 13, wherein said metallic atoms are selected from the group consisting of boron, gadolinium, and platinum.
15. The method of claim 13, wherein said polysaccharide is selected from the group consisting of galactose, rhamnose, mannose or a combination thereof.
16. The method of claim 13, wherein said polysaccharide can chelate from about 1 to about 100 metallic atoms.
17. The method of claim 13, wherein said nuclear particle is an alpha particle.
18. The method of claim 17, wherein said alpha particle has approximately 1.7 MeV.
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US56176904P | 2004-04-13 | 2004-04-13 | |
PCT/US2005/012388 WO2005107387A2 (en) | 2004-04-13 | 2005-04-13 | Targeting of radioimagining and radiotherapy agents |
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