CN101829340B - Medicine composition for treating solid tumors as well preparation method and application thereof - Google Patents
Medicine composition for treating solid tumors as well preparation method and application thereof Download PDFInfo
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Abstract
The invention provides a medicine composition for treating solid tumors, which is prepared from the following raw materials in proportion by weight: 1-4 parts of Na 131I and 5 parts of Na 125I. The invention also provides a preparation method and application of the medicine composition. The 131I in the medicine composition has a strong and transient function, the 125I has the characteristic of long half-life period (60 days), due to the addition of the 125I, the dosage of the 131I is reduced, environment pollution and protective difficulty are lowered, and the medicine composition can exert alocal radiation function for a long time to inhibit the recidivation and the metastasis of the tumors. The mixture of the 131I and the 125I enhances the energy of rays, extends the aging of the medicament so that the medicament can achieve the purposes of directional and continuous radiotherapy in the tumors and application as a tracer.
Description
Technical field
The present invention relates to a kind of pharmaceutical composition of treating entity tumor.Belong to drug world.
Background technology
According to The World Health Organization's data, the whole world has 1,000 ten thousand New Development tumor patients, 6,000,000 people to die from malignant tumor every year approximately, and the sickness rate of malignant tumor also increases progressively in the amplitude with annual 1.8-4%.Malignant tumor has become the cardiovascular and cerebrovascular disease that continues, occupies the tertiary cause of death after the infectious disease.Even through effort for many years, the prognosis of many malignant tumor does not have significant improvement yet, and malignant tumor remains global difficult medical problem in present and a very long time from now on.In China, because hepatitis B popular in the past, make hepatitis B have the sickness rate of primary hepatocarcinoma of direct etiology and pathology contact high; Along with Chinese people's living standard raising, life style is westernization gradually, and the sickness rate of the malignant tumor of cancer of pancreas and cancer of bile ducts and other systems is also in rising trend; Under existing treatment means; The malignant tumor patient of most liver and gall pancreas system is dead in morbidity 1 year, like 30.6 ten thousand people that fall ill in the hepatocarcinoma year of China, and year dead 30.0 ten thousand people; 3.3 ten thousand people that fall ill in the cancer of pancreas year of the U.S., year dead 3.2 ten thousand people.How to treat emphasis and difficult point that malignant tumor is medical research always.
The Therapeutic Method of malignant tumor mainly comprises excision at present, X-ray therapy, chemotherapy and various comprehensive treatment, and wherein excision is first-selected Therapeutic Method; But most of malignant tumor patients have been in the middle and advanced stage of tumor when diagnosing, and the chance of ocal resection is little, and for example primary hepatocarcinoma excision rate is less than 10%; Cancer of pancreas is less than 15%; And excision not only expense is high, painful big, the prognosis of postoperative is also undesirable.5 years survival rates of postoperative of hepatocarcinoma are at 20-45% at present; And 5 years survival rates of the postoperative of cancer of pancreas are less than 15%; Most of patients can only be treated through non-operative treatment, and the malignant tumor of liver and gall pancreas system is dark because of the position, and conventional outer radiation is relatively poor because of the shielding effect of rib; Again because of liver and digestive tract to the very responsive radiation damage that suffers easily of lonizing radiation; Make liver and gall pancreas system become outer radiocurable relative forbidden zone, liver and gall pancreas malignant tumor is low to the sensitivity of most of chemotherapeutics, and for example the approval of American National Food and Drug Admistraton is used to treat the standard drug gemcitabine of cancer of pancreas; The new drug Ge Lifeini of treatment primary hepatocarcinoma, its clinical effective rate is all less than 20%.Therefore press for and seek non-operative treatment new method evident in efficacy.Domestic in recent years part large hospital begins to introduce produced in usa
125I metal casing nucleic particle is treated multiple solid malignant, particularly cancer of pancreas through the mode that tumor is implanted into; Hepatocarcinoma; Bone tumor etc. have obtained effect preferably, but this particle is very expensive, one of more than 400 yuan of RMB of domestic price; A patient accomplishes the common total cost of treatment and reaches 2-3 ten thousand, and the said firm has reached more than 1,000,000,000 yuan in the annual sales amount of China at present.Because most of nucleic have strong toxicity, as
90Y,
89Sr has intensive close bone property, in case disengage being gathered in the osseous tissue, destroys myeloid tissue, and the probability that causes aplastic anemia is arranged;
32P can be by the most of tissue absorption of body, and cause that body damages widely, thus at present in the world the carrier of plesioradiotherapy all adopt metal, glass, pottery etc.; The nucleic sintering is buried in it; To reduce the release of nucleic, in vivo can not degrade, technical operation is complicated; Distributivity is poor, costs an arm and a leg.The nucleic medicine that is used at present to treat tumor abroad has:
90The Y glass microsphere
In 1999 through U.S. food Drug Administration (FDA) authentication, be used to treat can't excision liver cancer patient.
90The Y resin microsphere
Passed through U.S. food drug surveilance pipe (FDA) authentication in 2002, with the metastatic liver cancer of fluorouracil therapeutic alliance colorectal carcinoma.
125I nucleic particle has been write instructions and transfer through U.S. food drug surveilance pipe (FDA) authentication and has been used for treatment of prostate cancer.Above-mentioned nucleic particle or microsphere are carrier with metal or glass all, and specific gravity of glass is big, and perfusion is difficulty relatively, and it is not good to distribute, the radioactivity tumor: liver is than (T: N) relatively low.Metal or glass can't be degraded, and are stranded in for a long time in vivo, have both influenced perfusion therapy once more, and its tissue injury's effect at a specified future date also remains to be observed; Such as
32The P glass microsphere can cause liver portal area connective tissue to thicken, and insufferable abdominal distention symptom appears in the patient clinically.
90The Y glass microsphere half-life is lacked (64.1 hours), and specific radioactivity is not high.
90The Y glass microsphere discharges pure beta ray can't externally monitor, thus must use simultaneously technetium-99 (
99mTc) protein microsphere of labelling confirms that the blood of tumor supplies and radioactivity tumor liver ratio,
90The Y glass microsphere must could obtain radioactive activity after the activation in the linear accelerator of special use, its short half-life has limited it with expensive activation equipment and can only use in bigger medical center.
90The Y glass microsphere is the foreign patent product, costs an arm and a leg, and domestic being difficult to promotes.
Be used for the tumor implanted treatment at present
125I nucleic particle can only be spot distribution, and it is difficult to reach radical result skewness and spreadability official post.Disperse is effective between the gelatine microsphere tissue that particle diameter is little in theory, can be ribbon or column after the injection and distribute, thereby increase the coverage rate and the completeness of internal radiotherapy.There is bibliographical information to adopt
131I is used for the tumor implanted treatment, still
131I has the energy height, and strong to the lethal effect of tumor cell, environmental pollution is big, must use in special radioactivity protection ward, and
131The half-life of I short (8 days), and
125I usually can not spike because imaging is bad.
Summary of the invention
Technical scheme of the present invention has provided a kind of pharmaceutical composition of treating entity tumor.The invention provides this preparation of drug combination method and purposes.
The invention provides a kind of pharmaceutical composition of treating entity tumor, it is the preparation that is prepared from the following weight proportion raw material:
Na
131I 1-4 part, Na
1255 parts of I.
Further preferably, its preparation of being prepared from the following weight proportion raw material:
Na
1312.5 parts of I, Na
1255 parts of I.
Wherein, described preparation is injection, microsphere.
Wherein, described microsphere is a gelatine microsphere.
Wherein, every mg microsphere contains in the described gelatine microsphere
131The radioactivity of I is 0.02862-0.064mCi,
125The radioactivity of I is 0.04064-0.0927mCi.
Further preferably, every 50mg microsphere contains in the described gelatine microsphere
131The radioactivity of I is 1.744 ± 0.171mCi,
125The radioactivity of I is 2.477 ± 0.243mCi.
Further preferably, every 20mg microsphere contains in the described gelatine microsphere
131The radioactivity of I is 1.139069 ± 0.109841Ci,
125The radioactivity of I is 1.61775 ± 0.155925mCi.
Wherein, the particle diameter of described gelatine microsphere is 20-70 μ m.
The present invention also provides a kind of method for preparing the pharmaceutical composition of described treatment entity tumor, and the method for preparing of described gelatine microsphere is:
A. gelatine microsphere:
Get liquid paraffin, add Arlacel-80, put into round-bottomed flask, put in 55 ℃ of water-baths; 10% the gelatin solution speed with 30 droplets/minute under 550 rev/mins mechanical agitation of getting slowly splashes in the paraffin liquid; Stir and after 15 minutes aforesaid liquid is cooled to 4 ℃ rapidly, stir to add glutaraldehyde cross-linking, add acetone dehydration back sucking filtration again, thus obtained microsphere is with acetone twice, sucking filtration, and the screening preservation of the air-dry back of room temperature is subsequent use;
B, microsphere labelling
0.2mmol/L sodium dihydrogen phosphate and 0.2mmol/L sodium hydrogen phosphate are mixed with the buffer solution (PBS) of pH=7.0, the amp-T of preparation 20mg/ml chlorine, 15mg/ml sodium metabisulfite; Get microsphere to reaction tube, add the PBS swelling; With Na
131I and Na
125I presses 1-4 part: 5 weight proportion adds, and adds the amp-T of chlorine again, and the reaction of room temperature magnetic agitation adds the sodium metabisulfite stopped reaction; 4400 rev/mins centrifugal 4 minutes, abandon supernatant, gained labelling microsphere with normal saline clean, air-dry, it is subsequent use to sterilize.
The present invention also provides the purposes of this pharmaceutical composition in the medicine of preparation treatment hepatocarcinoma, renal carcinoma, breast carcinoma, thyroid carcinoma, cancer of pancreas, gastrointestinal solid tumor or orthopaedics tumor.
The present invention also provides the purposes of described pharmaceutical composition in the agent of preparation neoplasm tracing.
The present invention adopts
131I with
125I is clinical nucleic of treating tumor for many years; Compare with other nucleic,
131I with
125The great advantage of I is that toxicity is low: the main in vivo passive armor shape glandular tissue of iodine absorbs, and seldom stops at its hetero-organization, is not mainly excreted through urinary system by the iodine of thyroid picked-up in the serum.Oral Na when clinical treatment first cancer, hyperthyroidism
131I (iodine 131 sodium) millicuries up to a hundred do not have serious tissue injury yet.On the other hand, give the oral sealing parathyroid tissue of IodineSodium Solution (Compound Iodine Solutlon) before the art and can stop its reuptake radioiodine effectively, thereby prevent the thyroid damage.In addition, thyroid has stronger self repair ability, and the radiolesion of certain limit can be by himself rapid reparation, and therefore, the radioiodine nucleic is safer than other nucleic.
The present invention will adopt degradable protein gelatin microsphere as nucleic and pharmaceutical carrier; Gelatin is the product of collagen protein partial hydrolysis, but good biocompatibility, the multiple radionuclide of biodegradable stable bond and medicine (like chemotherapeutics, bioactive macromolecule etc.) are arranged; , combine with the radioiodine nucleic as carrier with gelatine microsphere, the employing group is established route of administration, can carry out plesioradiotherapy to the malignant tumor of multiple character; The microsphere of 20-70 μ m can distribute between tumor tissues through the method for tumor body injection more equably, can comprise hepatocarcinoma to various solid tumors; Renal carcinoma, breast carcinoma, thyroid carcinoma; Cancer of pancreas, the gastrointestinal solid tumor, the orthopaedics tumor is carried out tumor body implantable brachytherapy radiotherapy etc.After nucleic had decayed, gelatin is degraded gradually in vivo, and the nucleic that has decayed excretes through urinary system.But gelatine microsphere high concentration binding radioactivity iodine.
131The effect of I by force but ofer short duration,
125The adding of I can reduce
131The consumption of I, thus the difficulty of environmental pollution and protection reduced, and
125I has the characteristics of long half time (60 days), for a long time partial radiation effect and suppress the recurrence and the transfer of tumor.
131I with
125The mixing of I, under specific consumption proportion, the ray characteristics of two kinds of isotope releases are replenished each other, make it better meet the oncotherapy principle.
131The high-energy gamma ray of I can clearly video picture on SPECT, thus help microsphere that the doctor accurately understands implantation in tumor with intravital distribution; Will
131I with
125I mixed mark nucleic protein microsphere is implanted hepatocarcinoma through getting involved promoting the circulation of blood pipe perfusion thromboembolism or injection, in the pancreatic tumour tissue and microsphere more stable bonded
131I with
125I discharges gamma-rays in the part, can reach directed and lasting tumor internal radiotherapy and as the purpose of tracer.
Description of drawings
Fig. 1: postoperative rabbit 100ul serum r counting
Fig. 2: postoperative rabbit 100ul urine γ counting
Fig. 3: postoperative
131The peak SPECT video picture of I ability, 306KeV, window width 15%, developing time 2 minutes.A: postoperative 1 day, B: postoperative 8 days, C: postoperative 16 days, D: postoperative 24 days, E: postoperative 32 days, F: postoperative 48 days was the radionuclide imaging that does not have outstanding background
Fig. 4: postoperative double labelling microsphere liver implantation T-A curve (
131The ability peak of I)
Fig. 5: postoperative adopted in 48 days
125I's can scan 35KeV, window width 15%, developing time 2 minutes by the capable SPECT in peak.Find Hepar Leporis seu Oryctolagi position video picture.
Fig. 6: pathological section is HE dyeing, 200 times.A: postoperative 1 day, B: postoperative 8 days, C: postoperative 16 days, seeing microsphere has degraded, shown in the figure upward arrow; D: postoperative 32 days, the injection site is by fibers encapsulation; E: postoperative 48 days, the microsphere form is still complete.
Fig. 7 rabbit CT scan three-dimensional reconstruction, shown in " ten " word, the plantation tumor is low-density among the figure, and the border is clear.
SPECT/CT merges 3-D view behind Fig. 8 hepatic artery interventional therapy, shows that radionuclide concentrates in tumor locus (among the figure shown in the cross), and A is 16 days, and B is 24 days.
1 day Hepar Leporis seu Oryctolagi injection site necrosis of the direct liver injection microsphere of Fig. 9 microsphere of the present invention postoperative situation
Figure 10 microsphere results of interventional treatment of the present invention: wherein, A hepatic arteriography, conduit accurately get into Hepatic artery.B: radiography behind the thromboembolism, see that tiny tremulous pulse does not develop (arrow indication among the figure) in lines, explains that it is by the microsphere thromboembolism.
The specific embodiment
Embodiment 1 please provide the detailed method for preparing of microsphere of the present invention
One, crude drug:
Na
131I, Na
125I (sodium iodide)
Medical Type B gelatin:
SigmaA type gelatin label
50g LOT2011/04 ?BIOSHARP
Microsphere adopts the preparation of improvement emulsifying condensation method.With Na
131I and Na
125I adds in 1: 5～4: 5 ratio, bottles behind the chloramine-t method labelling.
Concrete method for preparing is:
1. microsphere is made
Adopt the preparation of improvement emulsifying condensation method.Get the 80ml liquid paraffin, add the 0.8ml Arlacel-80, put into round-bottomed flask, put in 55 ℃ of water-baths.10% the gelatin solution 10ml speed with 30 droplets/minute under 550 rev/mins mechanical agitation of getting slowly splashes in the paraffin liquid.Stir and after 15 minutes aforesaid liquid is cooled to 4 ℃ rapidly, continue to stir 8 minutes adding 3ml glutaraldehyde cross-linkings, continue to stir 22 minutes; Add 30ml acetone dehydration sucking filtration after 15 minutes again; Thus obtained microsphere is with acetone twice, sucking filtration, and room temperature air-dry back screening is preserved subsequent use.
2. microsphere labelling
Adopt the chloramine-t method labelling
131I,
125I.0.2mmol/L sodium dihydrogen phosphate and 0.2mmol/L sodium hydrogen phosphate are mixed with the buffer solution (PBS) of PH=7.0, the amp-T of preparation 20mg/ml chlorine, 15mg/ml sodium metabisulfite.Take by weighing the 50mg microsphere to reaction tube, added 190ul PBS swelling 10 minutes.With Na
131I and Na
125I adds in 1: 2 ratio, adds the 200ul chloramine-T again, and room temperature magnetic agitation reaction 30 minutes adds 200ul sodium metabisulfite stopped reaction.4400 rev/mins centrifugal 4 minutes, abandon supernatant, gained labelling microsphere is air-dry after cleaning 7 times with normal saline, the Co60 illumination-based disinfection is subsequent use.
Two, main component and toxic and side effects:
Gelatine microsphere: being made up of animal collagen, is that prolonged application is in clinical biomaterial.Mainly engulf processing by the intravital protease hydrolysis absorption of people or by phagocyte.No obvious toxic-side effects.
131 I: have two kinds of lonizing radiation of β and γ.With the β ray is master's (accounting for more than 99%), and gamma-rays is lower than 1%.
125 I: have low-yield γ and X ray, long half time, basic non-environmental-pollution.
Three, the dosage form of medicine and specification:
Dosage form: pacify bottled dried powder preparation, soak the back with normal saline before using and supply injection
The dry microspheres nt wt net weight; 1000mg (milligram)
Radioactivity: 30+/-2mCi (millicurie) (
131I with
125The radioactivity ratio of I is between 20-30%:80-70%)
Four, principal indication, usage, consumption:
A) be mainly used in the hepatocarcinoma of each phase clinically, cancer of pancreas, breast carcinoma, thyroid carcinoma, renal carcinoma, gynecological and urinary system malignant tumor etc.
B) adopt the intervention method through arterial thrombosis (like hepatocarcinoma and renal carcinoma), through CT B ultrasonic guiding injected method tumor is implanted into or abdominal in direct-view injected method tumor be implanted into (like cancer of pancreas, breast carcinoma etc.).To pacify bottle before the use earlier and press routine disinfection, and, soak and made the abundant imbibition of microsphere in 10 minutes with normal saline 10ml injection ampere.Adopt perfusion of ordinary syringe tremulous pulse fixed point or intratumor injection then.
C) dosage of implanting is reference with the radioactivity.With 1 millicurie/5cm
3(tumor tissue) is effective dose.According to tumor size decision radioactivity accumulated dose.Big tumor can adopt the mode of interval procedure to carry out.
Embodiment 2 double labelling microspheres of the present invention can be measured at the peak
The flag data of table 1:50mg double-label experiment.Data use the U.S. CAPINTEC.INC company medical activity meter of CRC-15R to measure." just add " the initial addition that refers to radioiodine, the mCi of unit, " whole survey " digit synbol is accomplished, and uses the ability peak of 131I and the ability peak data measured of 125I after washing is accomplished respectively, the mCi of unit.
| Sample number | 1 | 2 | 3 | 4 | 5 | 6 |
| Just add 131I | 2.14 | 2.139 | 2.234 | 1.786 | 2.214 | 2.226 |
| Just add 125I | 4.126 | 4.039 | 4.129 | 4.114 | 4.304 | 4.305 |
| Survey 131I eventually | 1.431 | 1.492 | 1.732 | 1.893 | 1.634 | 1.578 |
| Survey 125I eventually | 2.032 | 2.119 | 2.459 | 2.689 | 2.32 | 2.241 |
| Sample number | 7 | 8 | 9 | 10 | 11 | 12 |
| Just add 131I | 2.229 | 2.23 | 2.226 | 2.227 | 2.219 | 2.222 |
| Just add 125I | 4.289 | 4.283 | 4.272 | 4.21 | 4.23 | 4.161 |
| Survey 131I eventually | 1.894 | 1.771 | 1.734 | 1.839 | 1.594 | 1.974 |
| Survey 125I eventually | 2.69 | 2.516 | 2.463 | 2.612 | 2.264 | 2.803 |
| Sample number | 13 | 14 | 15 | 16 | 17 | 18 |
| Just add 131I | 2.226 | 2.228 | 2.222 | 2.222 | 2.233 | 2.158 |
| Just add 125I | 4.416 | 4.342 | 4.502 | 4.513 | 4.451 | 4.445 |
| Survey 131I eventually | 2.006 | 1.906 | 1.869 | 1.819 | 1.66 | 1.614 |
| Survey 125I eventually | 2.849 | 2.707 | 2.655 | 2.584 | 2.357 | 2.292 |
| Sample number | 19 | 20 | 21 | |||
| Just add 131I | 2.174 | 2.182 | 2.192 | |||
| Just add 125I | 4.447 | 4.467 | 4.425 | |||
| Survey 131I eventually | 1.497 | 1.971 | 1.718 | |||
| Survey 125I eventually | 2.126 | 2.799 | 2.441 |
Can know by table, contain in the 50mg gelatine microsphere of the present invention
131The radioactivity of I is 1.431-2.006mCi,
125The radioactivity of I is 2.032-2.849mCi.
Through pharmacodynamics test invention, in the described gelatine microsphere
131The radioactivity of I is 1.744 ± 0.171mCi,
125The radioactivity of I is the scope of 2.477 ± 0.243mCi, has best drug effect and spike effect simultaneously.
Through different first dosages
125I with
131I labelling 20mg gelatine microsphere, experimental result is following:
20mg gelatine microsphere labelling experiment:
| Sample number | 1 | 2 | 3 | 4 | 5 | 6 |
| Just add 131I | 2.568 | 2.584 | 2.576 | 2.569 | 2.492 | 2.511 |
| Just add 125I | 5.52 | 5.418 | 5.517 | 5.669 | 5.124 | 5.192 |
| Survey 131I eventually | 1.253 | 1.156 | 1.306 | 1.214 | 1.133 | 1.28 |
| Survey 125I eventually | 1.779 | 1.642 | 1.854 | 1.724 | 1.61 | 1.818 |
| Sample number | 7 | 8 | 9 | 10 | 11 | 12 |
| Just add 131I | 2.534 | 2.56 | 2.56 | 2.59 | 2.312 | 2.584 |
| Just add 125I | 5.187 | 5.752 | 5.108 | 5.44 | 5.462 | 5.419 |
| Survey 131I eventually | 1.13 | 1.274 | 0.9895 | 1.128 | 0.9915 | 1.099 |
| Survey 125I eventually | 1.605 | 1.81 | 1.405 | 1.602 | 1.408 | 1.561 |
| Sample number | 13 | 14 | 15 | 16 | Mean | Standard deviation |
| Just add 131I | 2.613 | 2.494 | 2.503 | 2.527 | 2.536063 | 0.070234 |
| Just add 125I | 5.438 | 5.716 | 5.666 | 5.224 | 5.42825 | 0.211474 |
| Survey 131I eventually | 1.11 | 1.102 | 0.9201 | 1.139 | 1.139069 | 0.109841 |
| Survey 125I eventually | 1.576 | 1.566 | 1.307 | 1.617 | 1.61775 | 0.155925 |
Can know that by table every 20mg microsphere contains
131The intensity of radiation of I is 0.9201-1.28mCi,
125The intensity of radiation of I is 1.307-1.854mCi.Further preferably, every 20mg microsphere contains
131The intensity of radiation of I is 1.139069 ± 0.109841Ci,
125The intensity of radiation of I is 1.61775 ± 0.155925mCi.
Below prove beneficial effect of the present invention through concrete effect experiment.
Test Example 1 medicine effect experiment of the present invention
1. distribute in the animal body of iodine isotope double labelling protein microsphere
Every laboratory animal rabbit is all accepted abdominal.With the double labelling gelatine microsphere of embodiment 1 preparation (
131I is 1.744 ± 0.171mCi,
125I is 2.477 ± 0.243mCi) implantation rabbit livers.
1.1 rabbit anteserum radioactivity monitoring
4 rabbit ear edge of postoperative picked at random every day venous blood collection 1ml accurately gets supernatant 100 μ l after centrifugal for 4400 rev/mins, measures the γ counting.Result such as Fig. 1:
According to the numerical value of serum time-γ counting each point, find that it meets pharmacokinetic two-compartment model, adopt 1stOpt software to carry out curve fitting, try to achieve its pharmacokinetics lonizing radiation blood level formula and be:
C＝6281.0321e
-0.5382t+548.1884e
-0.0411t
t
(1/2) α=1.2876 (my god)
t
(1/2) β=16.86 (my god)
K
21＝0.0810
K
10＝0.2731
K
12＝0.2252
1.2 rabbit urine radioactivity monitoring result such as Fig. 2:
1.3SPECT total body opacification
Postoperative 4 hours and the 1st, 4,8,16,24,32,48 day each group adopt Philip Skylight SPECT total body opacification by West China Nuclear Medicine Department of hospital, ability peak 364KeV, window width 15%; 1 times of amplification; Matrix 64 * 64, preceding bit scan, acquisition time 2 minutes (Fig. 3:
131I SPECT video picture).The ROI program is used in each time imaging, delineates liver, measures its radiocounting (table 3), and is abscissa with time, and ordinate value is by following calculating: (each time point liver counting-background count)/(liver counting-background count in first day), drafting
131Time-radioactivity of I (time-activity curve, T-A) curve.Measure each time point counting of thyroid and draw T-A curve (Fig. 4) with identical ROI.Postoperative 85,96,105 days, promptly
131I through 10 half-life (80 days) after, at this moment
131I can ignore, and adopts Philip Skylight SPECT video picture, ability peak 35KeV, all the other parameter constants.Can find this moment
125I still concentrate in the liver injection site (Fig. 5:
125I SPECT video picture).
SPECT video picture prompting, postoperative all can be known in 24 days and see that microsphere injection Hepar Leporis seu Oryctolagi position has that radioactivity is dense gathers.Postoperative was seen the thyroid faint development in zone in the 8th day and the 16th day.
Time-activity curve shows, As time goes on the radioactivity at liver position descends gradually, during to 24 days near background.The liver area radiocounting descended very fast at 1-8 days, descended slow relatively in 16-32 days.And the radioactivity in thyroid zone is very low from the beginning.Carry out curve fitting according to each time point data of ROI, the regression equation of asking is following:
Y=31875.51*0.832^x obtains the nucleic microsphere in liver organization
131The actual half-life of I is 4.449 days.
1.4 pathological examination
The liver specimens of putting to death animal was placed 10% formalin solution fixing 24～48 hours, FFPE, section, the pathology inspection is done in HE dyeing, sees Fig. 6.
2. iodine isotope double labelling protein microsphere is at VX
2Application in the Hepar Leporis seu Oryctolagi carcinoma transplanted model
The animal via femoral arteriography of VX2 Hepar Leporis seu Oryctolagi carcinoma transplanted model to Hepatic artery, is injected iodine isotope double labelling protein microsphere, and concrete grammar is:
The rabbit preserved skin is fixed in after the anesthesia on the intervene operation platform, dissects left side or right side inguinal region, isolates femoral artery.Insert the F-18 conduit, until the Hepar Leporis seu Oryctolagi tremulous pulse, inject the suspension of an amount of nucleic microsphere and 25% glucose, i.e. TAE (transcatheter arterial embolization is through the conduit arterial thrombosis) art (Fig. 7 A).The capable immediately radiography of postoperative is found Hepatic artery tiny branch thromboembolism (Fig. 7 B).Fig. 8, Fig. 9 are seen in row SPECT-CT inspection after accomplishing.
Experiment can be colonizated in implant site after showing that iodine isotope double labelling protein microsphere is implanted in the animal body; At trans-hepatic artery interventional therapy VX
2In the model of Hepar Leporis seu Oryctolagi carcinoma transplanted, can be good at being gathered in tumor locus.Isotope iodide does not all stop in its hetero-organization in two tests.Think that thus the treatment that iodine isotope double labelling protein microsphere is used for entity tumor is safely and effectively.
The effect experiment of Test Example 2 direct liver injection microspheres of the present invention
Directly necrosis is seen in 1 day Hepar Leporis seu Oryctolagi injection site of liver injection microsphere postoperative, and is shown in figure 10.Therefore, with microsphere treatment tumor of the present invention, can cause tumor tissue necrosis soon.
Report at present
131The gelatine microsphere intratumor injection of I and ametycin is to the therapeutic effect of mouse experiment property hepatocarcinoma, wherein
131The consumption of I is according to known reduction formula, and its consumption is 81.25 μ Ci/cm
3, in the tumor after the injection 7 days,
131I-MMC-GM is 58.7% to the suppression ratio of tumor growth; Because this dosage is to mice; If this dosage is used for rabbit; If by the conversion coefficient of medicine dose,equivalent between each animal and the people, the coefficient of mice and rabbit is 2.7, then the consumption of rabbit should be 81.25*2.7=219.375 μ Ci: in the pharmaceutical composition of the present invention
131The amount that I is used for rabbit is about 82 μ Ci/cm
3, with
125The I compatibility uses,
131The consumption of I obviously reduces, and has brought into play synergistic function, with prior art report
131The I-MMC-GM gelatine microsphere is compared, and onset is obviously accelerated.
That above-mentioned evidence, medicine microspheres of the present invention can reach simultaneously is directed, continue the tumor internal radiotherapy and as the purpose of tracer.
Claims (11)
1. pharmaceutical composition of treating entity tumor, it is characterized in that: it is the preparation that is prepared from following raw materials by weight proportions:
Na
131I 1-4 part, Na
1255 parts of I.
2. the pharmaceutical composition of treatment entity tumor according to claim 1 is characterized in that: the preparation that it is prepared from following raw materials by weight proportions:
Na
1312.5 parts of I, Na
1255 parts of I.
3. the pharmaceutical composition of treatment entity tumor according to claim 1 and 2 is characterized in that: described preparation is injection, microsphere.
4. the pharmaceutical composition of treatment entity tumor according to claim 3 is characterized in that: described microsphere is a gelatine microsphere.
5. the pharmaceutical composition of treatment entity tumor according to claim 4 is characterized in that: every mg microsphere contains in the described gelatine microsphere
131The radioactivity of I is 0.02862-0.064mCi,
125The radioactivity of I is 0.04064-0.0927mCi.
6. the pharmaceutical composition of treatment entity tumor according to claim 5 is characterized in that: every 50mg microsphere contains in the described gelatine microsphere
131The radioactivity of I is 1.744 ± 0.171mCi,
125The radioactivity of I is 2.477 ± 0.243mCi.
7. the pharmaceutical composition of treatment entity tumor according to claim 5 is characterized in that: every 20mg microsphere contains in the described gelatine microsphere
131The radioactivity of I is 1.139069 ± 0.109841Ci,
125The radioactivity of I is 1.61775 ± 0.155925mCi.
8. according to the pharmaceutical composition of any described treatment entity tumor of claim 4-7, it is characterized in that: the particle diameter of described gelatine microsphere is 20-70 μ m.
9. method for preparing the pharmaceutical composition of any described treatment entity tumor of claim 4-8, it is characterized in that: the method for preparing of described gelatine microsphere is:
A. gelatine microsphere:
Get liquid paraffin, add Arlacel-80, put in 55 ℃ of water-baths; 10% the gelatin solution speed with 30 droplets/minute under 550 rev/mins mechanical agitation of getting slowly splashes in the paraffin liquid; Stir and after 15 minutes aforesaid liquid is cooled to 4 ℃ rapidly, stir the adding glutaraldehyde cross-linking, add acetone dehydration back sucking filtration again, thus obtained microsphere is used acetone, sucking filtration, and the screening preservation of the air-dry back of room temperature is subsequent use;
B, microsphere labelling
0.2mmol/L sodium dihydrogen phosphate and 0.2mmol/L sodium hydrogen phosphate are mixed with the buffer solution of pH=7.0, preparation 20mg/ml chloramine-T, 15mg/ml sodium metabisulfite; Get microsphere to reaction tube, add said buffer solution swelling; With Na
131I and Na
125I presses 1-4 part: 5 weight proportion adds, and adds chloramine-T again, and the reaction of room temperature magnetic agitation adds the sodium metabisulfite stopped reaction; 4400 rev/mins centrifugal 4 minutes, abandon supernatant, gained labelling microsphere with normal saline clean, air-dry, it is subsequent use to sterilize.
10. the purposes of any described pharmaceutical composition of claim 1-8 in the medicine of preparation treatment hepatocarcinoma, renal carcinoma, breast carcinoma, thyroid carcinoma, cancer of pancreas, gastrointestinal solid tumor or orthopaedics tumor.
11. the purposes of any described pharmaceutical composition of claim 1-8 in the agent of preparation neoplasm tracing.
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| CN101338303A (en) * | 2008-08-29 | 2009-01-07 | 四川大学华西医院 | Adenovirus marked by radionuclide |
| CN101417135A (en) * | 2008-11-20 | 2009-04-29 | 同济大学 | Preparation method of biodegradable fallout radioactive material for treating cancer |
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| CN101417135A (en) * | 2008-11-20 | 2009-04-29 | 同济大学 | Preparation method of biodegradable fallout radioactive material for treating cancer |
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| Title |
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| 陈晓理等.《用结合131碘和化疗药物的明胶微球作肝动脉栓塞治疗晚期肝癌9例报告》.《华西医大学报》.1992,第23卷(第4期),第420-423页. * |
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