CN106344939A - Preparation method and application of radioiodinated biodegradable chitosan-collagen composite microsphere medicine - Google Patents
Preparation method and application of radioiodinated biodegradable chitosan-collagen composite microsphere medicine Download PDFInfo
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Abstract
The invention discloses a composite microsphere. The composite microsphere is formed in a way that chitosan and collagen are combined. The invention further discloses a radioactive microsphere for radioactive therapy, and radionuclides are marked on the microsphere. The invention further discloses a preparation method and application of the microsphere. According to the composite microsphere, the preparation method and the application, a biodegradable chitosan-collagen composite microsphere is used as nuclide and a drug carrier, both the chitosan and the collagen have good biocompatibility, are biodegradable and can be stably combined with a plurality of radionuclides and drugs (such as chemotherapy drugs, bioactive macromolecules and the like), and clinical application prospects are good.
Description
Technical field
The present invention relates to a kind of preparation side of the Biodegradable chitosan of radioiodination-collagen composite microsphere drug
Method and purposes.
Background technology
According to World Health Organization (WHO) (who) data, malignant tumor leads to year death toll more than 6,200,000 people, the whole world is every
Year there are about 1100 Wan Xinfa tumor patients, and the sickness rate of malignant tumor is also being incremented by with the amplitude of annual 1.8-4%, pernicious swollen
Tumor has become and has occupied deputy worldwide Disease causation after cardiovascular and cerebrovascular disease.On the Asia ground including China
Area, high with the sickness rate of the primary hepatocarcinoma that hepatitis B has direct Correlation between Pathology；And the life recently as Chinese people
Running water is put down and is improved, and the sickness rate of the malignant tumor of cancer of pancreas and cancer of bile ducts and other system is also in rising trend, controls existing
Under treatment means, dead, the hepatocarcinoma year morbidity 33 of China in morbidity 1 year of the malignant tumor patient of most liver and gall pancreas system
Ten thousand people, year dead 300,000 people, how to treat malignant tumor and be always the emphasis of medical research and difficult point.
The Therapeutic Method of malignant tumor mainly includes excision, X-ray therapy, chemotherapy and various Comprehensive Treatment side at present
Method, wherein excision are first-selected Therapeutic Method, but already in tumor when most of malignant tumor patient is diagnosed
Late period, perform the operation complete tumor resection probability very little, such as Surgical Resection of Hepatic Carcinoma rate less than 10%, cancer of pancreas less than
15%.And the prognosis of excision is also undesirable, postoperative 5 years survivals of current hepatocarcinoma are in 20-45%, and cancer of pancreas
Survival rate is less than 15% within postoperative 5 years.Clinically most of patients can only be treated by non-operative treatment at present, and liver and gall pancreas system
Malignant tumor is low to the sensitivity of most of chemotherapeutics, and the clinical effective rate of common chemotherapeutics is less than 20%；And tumor position
Put depth, effect is poor because of the shielding of rib for conventional outer radiation, liver and digestive tract are again more sensitive to lonizing radiation and easy
Suffer from radiation damage, make liver and gall pancreas system become the absolute forbidden area of fluconazole ear drops, therefore evident in efficacy in the urgent need to seeking
Non-operative treatment new method.
Recent year part large hospital begins to use radioembolization microsphere to be treated, and is implanted into by tumor stove
Mode treats multiple solid malignants, particularly cancer of pancreas, hepatocarcinoma, and bone tumor etc. has been achieved with preferable effect.Radioactivity
Embolism microball is mainly made up of two parts: plays medicine and wraps up the microsphere of slow releasing function and the radioactive nucleus playing therapeutical effect
Element.
Presently the most common radioembolization microsphere is the radionuclide particle of metal or glass envelope.External at present
Nucleic medicine for treating tumor has:90Y glass microspherePass through U.S.'s food and medicine in 1999
Surveillance Authority (fda) certification, for treatment cannot excision liver cancer patient.90Y resin microsphere
Pass through U.S.'s food and medicine supervision pipe (fda) certification, the hepatic metastasess with fluorouracil therapeutic alliance colorectal carcinoma in 2002
Cancer.But a series of current clinical radiation seeds implanted treatment, however it remains common problems.Firstly, since most of nucleic
There is strong toxicity, such as90y、89Sr has strong close bone, once disengage to be gathered in osseous tissue, destroys myeloid tissue,
There is the probability leading to aplastic anemia；32P by the most of tissue resorption of body, and can cause body widely to damage, institute
With the carrier of current plesioradiotherapy in the world all using metal, glass, pottery etc., nucleic sintering is buried in the inner,
To reduce the release of nucleic.Currently used for tumor implantation therapy125I nucleic particle or microsphere, due to preparation condition and intervention handss
The restriction of section, all with metal or glass as carrier, the nucleic particle granules of implantation larger (5mm about) can only be in spot distribution,
Perfusion relative difficulty, internal skewness, spreadability is poor, radioactivity tumor: organizes more relatively low than (t:n) it is difficult to reach very well
Internal radiotherapy effect.Secondly, metal or glass cannot be degraded, and prolonged stay is in the radioactivity that in vivo, result in implantation
Particle in vivo can not be degraded, and has both affected perfusion therapy again, also easily causes tissue injury's effect at a specified future date such as32P glass
Glass microsphere can lead to liver portal area connective tissue to thicken, and clinically insufferable abdominal distention symptom in patient.
Radiotherapy embolism microball to the major requirement of radionuclide is: tumor radiation dosage is high；Ray range is short, the half-life
Moderate, surrounding tissue and operator are affected less.Iodine as required a kind of necessary trace element in body metabolism, in body
Inside mainly absorbed by parathyroid tissue, seldom stop in its hetero-organization, in serum not by the iodine of thyroid uptake mainly through urinary system
System excretes.Na is administered orally when clinical treatment first cancer, hyperthyroidism131I (iodine 131 sodium) millicuries up to a hundred are also not result in serious
Tissue injury.Therefore, radioiodine nucleic is a kind of safe interior therapeutic radionuclide.Iodine has 4 kinds and possesses clinic
The radiosiotope of using value, iodine 123 (123I), iodine 124 (124I), I125 (125I) and iodine 131 (131I), wherein
Two kinds of conventional radioactive iodine isotope are I125 and iodine 131.60 days I125 half-life, Auger electron can be launched and compared with mental retardation
The gamma-rays of amount, wherein Auger electron ionized biological effect are strong, and internal radiation radius only has 10nm, is extremely outstanding interior irradiation
Treatment radionuclide；125I nucleic particle is write instructions and transfer for prostate by U.S.'s food and medicine supervision pipe (fda) certification
The implanted treatment of cancer.And the iodine 131 half-life slightly short (8.4 days), can launch 364kev gamma-rays be used for single photon localization diagnosises,
The β ray that 192kev also can be launched is used for treating, its internal radiation radius 0.9mm, to damaging surrounding tissue very little, is also a kind of
Preferably treatment nucleic.
Shitosan is a kind of material of degradable, has at present to wrap up using chitosan microball and Adsorption of Radioactive iodine, from
And prepared the Radiolabeled microsphere carrying radioiodine.But the mark rate of radioiodine is not in single chitosan microball
Height, actual efficacy is not good.
Content of the invention
In order to solve the above problems, the invention provides a kind of complex microsphere, the medicine for radiation treatment and its system
Preparation Method and purposes.
Complex microsphere of the present invention, it is the microsphere being composited by shitosan and collagen protein.
Described shitosan is 2:(1-4 with the mol ratio of collagen protein).
A diameter of 5～100 μm of described microsphere.
The present invention prepares the preparation method of aforementioned microsphere, and step is as follows:
(1) take shitosan and collagen protein, be prepared into solution；
(2) described for step (1) solution is made emulsion；
(3) the described emulsion of curing schedule (2), forms the microsphere of solidification；
(4) wash, separate the microsphere of solidification, you can.
Specifically, can prepare in accordance with the following steps:
Take shitosan, add in the acetic acid solution containing the 2% of collagen, the mol ratio according to shitosan and collagen is 2:
(1-4) ratio, shitosan is added in solution, stirring obtains water white transparency viscous solution；Will be sticky for aforementioned water white transparency molten
Liquid adds the liquid paraffin containing sorbitol anhydride oleate of 3.0～6.5 times of volumes of collagen solution, wherein, sorbitan
Oleate is 8:100 with the volume ratio of liquid paraffin, and stirring obtains emulsion liquid；To Deca collagen in emulsion under stirring
25% glutaraldehyde solution of 0.045～0.126 times of volume of solution is crosslinked, makes microsphere solidified forming；Products therefrom add different
Propanol rinse, the removal of impurity is gone in centrifugation；Products therefrom uses deionized water wash, and is filtered, is centrifuged, and concentrates, you can.
Present invention also offers purposes in preparing radiation treatment medicine for the aforementioned microsphere.
Present invention also offers for the Radiolabeled microsphere of radiation treatment, it is be marked with radionuclide aforementioned micro-
Ball.
Wherein, described radionuclide is radioiodine.
Wherein, described radioiodine123I,124I,125I or131i.
Wherein, the mark rate of described radionuclide is not less than 80%, preferably 81.27%～92.82%.
Wherein, the structure of described medicine is as follows:Wherein,
Radionuclide can be radioiodine.
The preparation method of foregoing pharmaceutical of the present invention, can be prepared as follows: step is as follows:
Take aforementioned microsphere, microsphere, it is that 7.0pbs solution is swelling that every 50mg microsphere adds 1ml ph, adds 5mci131i–
Nai, adding 50ul concentration is 20mg/ml chloramines-t, and room temperature magnetic force stirring reaction, after standing, adds in sodium metabisulfite
Only react；Centrifugation, abandons supernatant, gained labelling microsphere is carried out, lyophilizing, you can.
Present invention also offers purposes in the medicine of preparation treating cancer for the aforementioned Radiolabeled microsphere.
Wherein, described medicine is treatment hepatocarcinoma, renal carcinoma, breast carcinoma, thyroid carcinoma, cancer of pancreas, gastrointestinal solid tumor or orthopaedics
The medicine of tumor.
Present invention also offers purposes in preparing neoplasm tracing agent for the aforementioned Radiolabeled microsphere.
Present invention also offers a kind of pharmaceutical preparation for radiation treatment or spike, it is with aforementioned radiological predication fallout plot
Ball is active component, adds the preparation that pharmaceutically acceptable adjuvant or complementary composition are prepared from.
Wherein, described preparation is dried powder preparation, and every milligram of preparation contains 3 × 106～5 × 106Individual Radiolabeled microsphere.
The present invention is by the chitosan-collagen complex microsphere using degradable as nucleic and pharmaceutical carrier, shitosan and glue
Former be provided with good biocompatibility, biodegradable, can the multiple radionuclide of stable bond and medicine (as chemotherapeutics,
Bioactive macromolecule etc.)；With chitosan-collagen complex microsphere as carrier, combine with radioiodine nucleic, set using group
Route of administration, can carry out plesioradiotherapy to the malignant tumor of multiple properties, and 10-100 μm of microsphere can be noted by tumor body
The method penetrated relatively evenly is distributed between tumor tissues, can be to various solid tumors, including hepatocarcinoma, renal carcinoma, breast carcinoma, thyroid
Cancer, cancer of pancreas, gastrointestinal solid tumor, orthopaedics tumor carries out tumor body implantable brachytherapy radiotherapy etc..After nucleic has decayed, shitosan-glue
Former complex microsphere is gradually degraded in vivo, and the nucleic having decayed excretes through urinary system.
Chitosan-collagen complex microsphere can rely on the tyrosine stable bond radioiodine carrying on collagen, obtain height and put
Penetrating property is than the radionuclide preparation of degree；Chitosan-collagen complex microsphere can rely on the different ratio of raw material to adjust final preparation
Half-life in vivo, to adapt to the radioisotopic Half-life in vivo of labelling.
The present invention adopts131I and125I is the clinical nucleic treating tumor for many years；Compare with other nucleic,131I and125i
Great advantage be that toxicity is low: iodine is mainly absorbed by parathyroid tissue in vivo, seldom stops in its hetero-organization, in serum not by
The iodine of thyroid uptake mainly excretes through urinary system.Na is administered orally when clinical treatment first cancer, hyperthyroidism131I (iodine 131 sodium)
Millicuries up to a hundred do not have serious tissue injury yet.On the other hand, the preoperative IodineSodium Solution (Compound Iodine Solutlon) that gives is administered orally closing first
Shape glandular tissue can stop its reuptake radioiodine effectively, thus preventing thyroid microcancer.Additionally, thyroid have stronger
Itself repair ability, a range of radiolesion can be repaired rapidly by its own, and therefore, radioiodine nucleic is compared with other cores
Element is safer.
To sum up, chitosan-collagen complex microsphere of the present invention possess good biocompatibility, biodegradable, can stably tie
Close multiple radionuclides and medicine, and high with the combination rate of radioactive nuclide iodine, the iodine 131 labelling shitosan preparing-
Collagen composite microsphere is used for treatment and the spike excellent effect of tumor, and potential applicability in clinical practice is good.
Obviously, the above according to the present invention, according to ordinary technical knowledge and the customary means of this area, without departing from
Under the premise of the present invention above-mentioned basic fundamental thought, modification, replacement or the change of other various ways can also be made.
The specific embodiment of form by the following examples, remakes further specifically to the above of the present invention
Bright.But this scope being interpreted as the above-mentioned theme of the present invention should not be only limitted to Examples below.All based on the above of the present invention
The technology realized belongs to the scope of the present invention.
Brief description
The sign of the chitosan-collagen complex microsphere that Fig. 1 prepares.A, b be 10-20 μm of group microsphere 100 times of light microscopics and
Surface character under 1000 times of scanning electron microscopies；C, d are the table under 40 times of light microscopics and 1000 times of scanning electron microscopies of 20-60 μm of group microsphere
Region feature.
Radioiodination rate (a) of Fig. 2 chitosan-collagen complex microsphere is detected with stability (b).
The degradability of the chitosan-collagen complex microsphere that Fig. 3 prepares.
Fig. 4 histopathology evaluates the vivo biodistribution safety of chitosan-collagen microsphere.
The administering mode to primary hepatocarcinoma rat of Fig. 5 Radiolabeled microsphere.Intratumor injection (a) and proper hepatic artery perfusion
B () is administered.For macroscopic liver tumor position after rat laparotomy in a in figure white circle, intratumor injection infusion of medicine is herein；
B figure show area of rats'liver arteries branch, a. proper hepatic artery, b. gastroduodenal artery, c. common hepatic artery.Radioactivity
During microsphere injection, using area of mosquito forcepss temporary closure proper hepatic artery nearly branch, radiological predication fallout plot ball warp proper hepatic artery (a) is to entering
Liver direction is injected.
Fig. 6 original position Rats With Hepatoma accepts the survival curve after Radiolabeled microsphere treatment.Amount to 12, accept treatment 35 days
Afterwards, matched group existence number is 0, and hepatic arterial infusion administration group existence number is 2, and in tumor, administration group existence number is 3.
After Fig. 7 original position Rats With Hepatoma accepts treatment, liver compares, every group 4, and white arrow indication is macroscopic swollen
Tumor stove.
Fig. 8 original position Rats With Hepatoma compares sham operated rats, in-situ injection group after accepting treatment, the liver of Hepatic artery injection group swells
Tumor growing state.It is tumor focus partial enlarged drawing in red wire, yellow arrows are macroscopic tumor stove.
Fig. 9 original position Rats With Hepatoma detects the liver organization pathological section of iodine labeling complex microsphere after accepting treatment, he dyes.
Radiocounting in blood after the acceptance treatment of Figure 10 original position Rats With Hepatoma.
Radioiodination chitosan-collagen complex microsphere is injected into different time after rat original position hepatocarcinoma by Figure 11, right
Rat carries out whole body spect/ct image results.Radioiodination chitosan-collagen complex microsphere is injected into rat in situ
Different time after hepatocarcinoma, carries out whole body spect/ct imaging detection to rat131I signal, detection energy peak 364kev, window width 15%,
2 minutes sweep times.A. postoperative 7 days, postoperative 21 days of postoperative 14 days of b., c., postoperative 28 days of d..
Specific embodiment
Raw material and its purchase producer:
Corii Bovis seu Bubali i Collagen Type VI (mw～300000, Sichuan University's biomaterial center)；Shitosan (mw～190000-
310000, sigma-aldrich company of the U.S.)；Acetic acid (analyzes pure, Chengdu Ke Long chemical reagent factory)；Liquid paraffin (analysis
Pure, sigma company of the U.S.)；Span80 (sigma company of the U.S.)；Glutaraldehyde (25%, Chengdu Ke Long chemical reagent factory)；Isopropyl
Alcohol (analyzes pure, Guangzhou Jinhua big chemical reagent company limited)；Chloramines-t (Chengdu Ke Long chemical reagent factory)；Sodium metabisulfite
(Chengdu Ke Long chemical reagent factory)；Na131i solution (offer of Huaxi Hospital Attached to Sichuan Univ Nuclear Medicine Department)；Electronic balance
(esj120-4, Shenyang Longteng Electronic Co., Ltd.)；Df-101s heat collecting type constant-temperature heating magnetic stirring apparatus (90-2, Shanghai Hu Xi
Analytical Instrument Co., Ltd)；Refrigerated centrifuger (eppendorf 5702r, German gene company limited)；γ radioimmunity counts
Instrument (fj2021, Chinese Xi'an 262 instrument plant)；Fluorescence microscope (ckx41, Japanese olympus company)；Conventional glass, handss
Art vessel apparatus.
The preparation of embodiment 1 iodine 131 labelling chitosan-collagen complex microsphere of the present invention
1st, preparation method
Raw material: na131I, na125I (sodium iodide)；Shitosan；I Collagen Type VI；
(1), using improvement emulsifying condensation method preparation, concrete grammar is as follows for microsphere:
2:1 ratio takes shitosan and collagen protein in molar ratio, specifically, collagen protein is dissolved in 2% acetic acid solution
In, obtain the collagen solution that collagen concentration is 3.62mg/ml, then shitosan 10mg is added in 1.66ml collagen solution；2%
Water white transparency viscous solution is obtained after stirring 1h dissolving in acetic acid solution；This solution is slowly added to containing sorbitan Oleic acid
In the liquid paraffin (wherein, liquid paraffin 10ml, Sorbitol monoglyceride 0.8ml) of ester, obtain after 1h is stirred at room temperature
Emulsion liquid；Being slowly added dropwise 210ul concentration under stirring in emulsion is 25% glutaraldehyde solution crosslinking 1h, makes microsphere solid
Chemical conversion shape；Add sufficient isopropanol washing in products therefrom, centrifugation removes the impurity such as liquid paraffin, glutaraldehyde；Products therefrom
Using Enough Dl water cyclic washing, and filter through 100 μm of filters, be centrifuged, be finally concentrated to give shitosan collagen microsphere
Suspension., with 121 DEG C, after 15min autoclaving, aseptically lyophilizing is standby for thus obtained microsphere.Calculated using blood cell calculator and produce
Rate, microsphere yield is about 5,000,000/milligram.
Its particle diameter is 5-10 μm.
(2) radioiodination of chitosan-collagen complex microsphere
0.2mmol/l sodium dihydrogen phosphate and 0.2mmol/l disodium hydrogen phosphate are configured to the buffer solution of ph=7.0
(pbs)；Take 50mg microsphere to reaction tube, add 1mlpbs swelling；Add 5mci131I-nai (10～100mci), adds
50ul chloramines-t (20mg/ml), room temperature magnetic force stirring reaction 10 minutes, then after standing 30 minutes, add sodium metabisulfite
(15mg/ml) stopped reaction, subsequently now detects the mark rate of microsphere.3000g is centrifuged 4 minutes, supernatant, gained labelling microsphere
Clean 3-5 time with physiological saline solution to no free radioactivity isotope, standby in physiological saline solution.
2nd, mark rate detection
Detect microsphere mark rate mark rate using paper chromatography.Deca point 1ul microspheres solution at paper tape 2ml, by paper tape
It is placed in γ calculating instrument and its mark rate is detected.
Degradation curve in serum for the Radiolabeled microsphere such as Fig. 2 institute after the radioiodination rate labelling of this complex microsphere
Show.
As shown in Fig. 2 being catalyst using chloramines t, chitosan-collagen complex microsphere is carried out with the mark of radioactivity iodine 131
Note, the iodine 131 mark rate of microsphere is 92.82% (a).After microsphere after labelling is mixed with serum, 37 degree of standings, in different time
Free radiocounting (b) in point detection microsphere and serum.Result shows, the microsphere after 200 hours (8.4 days), in serum
Radiochemicsl purity is still stablized in a higher level (> 70%).
3rd, the main component of radioiodination chitosan-collagen complex microsphere of the present invention and toxic and side effects
The degradability of 3.1 chitosan-collagen microspheres:
The complex microsphere that 10mg is prepared mixes sealing, 37 DEG C of standings with 1ml serum, respectively 15, takes when 30,45 days
Sample, is characterized using scanning electron microscope observation microsphere.
As shown in figure 3, visible microsphere starts degraded after 15 days, deformation；After 30 days, microsphere is degraded further, after 45 days
Microsphere is degraded substantially.Which demonstrate our microspheres of preparation and there is degradability.
The vivo biodistribution safety evaluatio of 3.2 chitosan-collagen microspheres:
Microsphere is passed through hepatic arterial infusion or is injected directly into normal wista rat liver, after 30 days, take rat liver group
Knit and be placed in 10% formalin solution and fix 24～48 hours, paraffin embedding, section, he dyes, and makees pathological examination.
Histopathological examination result is as shown in figure 4, in the normal liver of direct injection (figure a), microsphere injections point is attached
Closely occur in that the medicine cavity that injection is formed, the dead cell that only a few leads to because of injection damage, drug injection occur in cavity
Most cellular morphologies around chamber are intact；Irrigate in the liver (figure b) of microsphere through proper hepatic artery, the thicker liver of blood vessel wall
Tremulous pulse (left side) defines obvious arterial thrombosiss, impacts without hepatic vein blood vessel (right side) relatively thin to blood vessel wall,
Thromboembolism tremulous pulse surrounding, hepatocyte still maintains intact cellular morphology.
This result confirms that our chitosan-collagen microsphere will not draw after direct injection or hepatic arterial infusion in vivo
The substantially death playing body cell is it was confirmed it is used for the biological safety of clinical practice.
The preparation of embodiment 2 iodine 131 labelling chitosan-collagen complex microsphere of the present invention
1st, preparation method
Raw material: na131I, na125I (sodium iodide)；Shitosan；I Collagen Type VI；
(1), using improvement emulsifying condensation method preparation, concrete grammar is as follows for microsphere:
Take shitosan and collagen protein in 1:1 ratio, specifically, collagen protein is dissolved in 2% acetic acid solution, obtains glue
Former protein concentration is the collagen solution of 3.62mg/ml, then shitosan 5mg is added in 3.3ml collagen solution；Will be slow for this solution
Add the liquid paraffin containing sorbitol anhydride oleate (wherein, liquid paraffin 10ml, Sorbitol monoglyceride 0.8ml)
In, obtain emulsion liquid after 1h is stirred at room temperature；Being slowly added dropwise 150ul concentration under stirring in emulsion is 25% penta
Dialdehyde solution crosslinking 1h, makes microsphere solidified forming；Add sufficient isopropanol washing in products therefrom, centrifugation removes liquid stone
The impurity such as wax, glutaraldehyde；Products therefrom uses Enough Dl water cyclic washing, and filters through 100 μm of filters, is centrifuged,
It is concentrated to give shitosan collagen microsphere suspensions eventually.Thus obtained microsphere with 121 DEG C, aseptically lyophilizing after 15min autoclaving
Standby.Yield is calculated using blood cell calculator, microsphere yield is about 5,000,000/milligram.
Its particle diameter is 5-15 μm.
(2) radioiodination of chitosan-collagen complex microsphere
0.2mmol/l sodium dihydrogen phosphate and 0.2mmol/l disodium hydrogen phosphate are configured to the buffer solution of ph=7.0
(pbs)；Take 50mg microsphere to reaction tube, add 1ml pbs swelling；Add131I-nai (10～100mci), adds chlorine
Amine-t (20mg/ml), room temperature magnetic force stirring reaction 10 minutes, then after standing 30 minutes, add sodium metabisulfite (15mg/ml)
Stopped reaction；3000g is centrifuged 4 minutes, abandons supernatant, and gained labelling microsphere physiological saline solution cleans 3-5 time and dissociates to nothing
After radiosiotope, standby in physiological saline solution.
2nd, mark rate detection
With embodiment 1.
After testing, in medicine of the present invention, iodine 131 mark rate is 81.27%.
The preparation of embodiment 3 iodine 131 labelling chitosan-collagen complex microsphere of the present invention
1st, preparation method
Raw material: na131I, na125I (sodium iodide)；Shitosan；I Collagen Type VI；
(1), using improvement emulsifying condensation method preparation, concrete grammar is as follows for microsphere:
1:2 ratio takes shitosan and collagen protein in molar ratio, specifically, collagen protein is dissolved in 2% acetic acid solution
In, obtain the collagen solution that collagen concentration is 3.62mg/ml, then shitosan 5mg is added in 3.3ml collagen solution；Should
Solution is slowly added to (wherein, liquid paraffin 20ml, the Sorbitol monoglyceride of the liquid paraffin containing sorbitol anhydride oleate
In 1.6ml), after 1h is stirred at room temperature, obtain emulsion liquid；Being slowly added dropwise 220ul concentration under stirring in emulsion is
25% glutaraldehyde solution crosslinking 1h, makes microsphere solidified forming；Add sufficient isopropanol washing in products therefrom, centrifugation removes liquid
The impurity such as body paraffin, glutaraldehyde；Products therefrom uses Enough Dl water cyclic washing, and filter through 100 μm of filters, from
The heart, is finally concentrated to give shitosan collagen microsphere suspensions.Thus obtained microsphere with 121 DEG C, after 15min autoclaving aseptically
Lyophilizing is standby.Yield is calculated using blood cell calculator, microsphere yield is about 5,000,000/milligram.
Its particle diameter is 10-100 μm.The concrete form of complex microsphere characterizes as shown in Figure 1.
(2) radioiodination of chitosan-collagen complex microsphere
0.2mmol/l sodium dihydrogen phosphate and 0.2mmol/l disodium hydrogen phosphate are configured to the buffer solution of ph=7.0
(pbs)；Take 50mg microsphere to reaction tube, add 1ml pbs swelling；Add125I-nai (10～100mci), adds chlorine
Amine-t (20mg/ml), room temperature magnetic force stirring reaction 10 minutes, then after standing 30 minutes, add sodium metabisulfite (15mg/ml)
Stopped reaction；3000g is centrifuged 4 minutes, abandons supernatant, and gained labelling microsphere physiological saline solution cleans 3-5 time and dissociates to nothing
After radiosiotope, standby in physiological saline solution.
2nd, mark rate detection
With embodiment 1.
After testing, in medicine of the present invention, I125 mark rate is 92.82%.
Embodiment 4 present invention contains the pharmaceutical preparation of iodine 131 labelling chitosan-collagen complex microsphere
The iodine 131 labelling chitosan-collagen complex microsphere of Example 1～embodiment 3 preparation, adds and pharmaceutically can connect
The adjuvant being subject to or complementary composition, make pharmaceutical preparation.
1. dosage form and specification
Dosage form: ampere bottled dried powder preparation, using front normal saline mixing for standby use.The stability of medicine
As shown in Figure 2.
Specification: 3～5 × 106Individual/mg (ten thousand microspheres of every milligram of 300-500).
Radioactivity: 50 ± 5mci/mg.
2. principal indication, usage, consumption:
A. clinically it is mainly used in hepatocarcinoma, cancer of pancreas, breast carcinoma, thyroid carcinoma, renal carcinoma, gynecological and the urinary system of each phase
System malignant tumor etc..
B. adopt intervention method Intra-arterial embolization (as hepatocarcinoma and renal carcinoma), through ct or b surpass the lower injection tumor of guiding be implanted into or
Look at lower injection tumor in abdominal straight and be implanted into (such as cancer of pancreas, breast carcinoma etc.).First ampulla is routinely sterilized using front, with life
Reason saline 10ml injection ampere, soaking makes the abundant imbibition of microsphere for 10 minutes.Then ordinary syringe tremulous pulse fixed point is adopted to fill
Note or intratumor injection.
C. the dosage implanted is with radioactivity as reference.With 0.5～5cm3/ mci (tumor tissue/millicurie) is effective agent
Amount, determines radioactivity accumulated dose according to tumor size.Larger tumor can be carried out by the way of interval procedure.
Beneficial effects of the present invention are described with the mode of experimental example below:
Experimental example 1 iodine 131 labelling chitosan-collagen complex microsphere of the present invention treats effect of hepatocarcinoma
The chitosan-collagen complex microsphere of the present invention of Example 1 preparation, verifies effect of its treatment hepatocarcinoma.
1) the animal hepatocarcinoma Experiment on therapy of iodine 131 labelling chitosan-collagen complex microsphere
A. rat primary liver cancer animal model is adopted to verify radioiodination chitosan-collagen complex microsphere of the present invention
Curative effect.The method for building up of rat primary liver cancer model is as follows:
The wista rat of 200-250g body weight, male and female half and half, raise in cleaning grade Animal House (cl level), in drinking water
Add the n- nitrosodiethylamine medicine of 1/1000 concentration (v/v), after induction 14-16 week, magnetic resonance imaging rat liver position,
Tuberosity number≤2 in liver, the rat of single tuberosity diameter≤3mm, it is considered as modeling successfully, include Experiment on therapy.
B., after modeling success, rat is randomly divided into 3 groups: be administered in situ in sham operated rats, hepatic arterial infusion group, and tumor
Group, concrete medication is as shown in Figure 5: rat opens abdominal cavity after 2% isoflurane anesthesia, compares magnetic resonance imaging image,
Find liver tumor focus；Sham operated rats do not carry out any process, complete abdominal cavity suture；Hepatic arterial infusion group is first under lobules of liver
Find the vessel branch area of proper hepatic artery (a), gastroduodenal artery (b), and common hepatic artery (c), Radiolabeled microsphere injects
When, using area of mosquito forcepss temporary closure branch, by Radiolabeled microsphere from land to enter liver direction injection proper hepatic artery (a)；
Original position administration group in tumor, is directly injected into Radiolabeled microsphere about 1,000,000 at tumor stove；Dosage is with radioactivity for ginseng
According to 0.5cm3/ mci is effective dosage.The method is essentially identical with clinical Hepatic cancer radiation treatment mode, can protect
Card medicine possesses the feasibility of clinical usage.
2) survival time of animals after iodine 131 labelling chitosan-collagen complex microsphere treats hepatocarcinoma compares
Administration finish after, all rats according to clean animal level standard (cl level) continue raise, until 3 groups in a certain group big
Experiment cut-off during all death in Mus.Record the life span of every group of rat, result is as shown in Figure 6.After operation 35 days, do evil through another person
Art group animal is all dead (0/4), hepatic arterial infusion group survival rate 50% (2/4), administration group survival rate 75% (3/4) in tumor.
3) the animal liverss pathological examination of iodine 131 labelling chitosan-collagen complex microsphere
Experiment on therapy collects all animal liverss after terminating, carry out perusal to rat liver in each group and compare and pathology
Learn detection to compare.Result such as Fig. 7, shown in 8, in sham operated rats, all overall gross distortion, swelling, rotten to the corn, liver in whole livers
Hardening, tumor has substantially diffused to full liver；In hepatic arterial infusion group, also different degrees of deformation swelling in liver, but deformation
Degree is light compared with sham operated rats, typically several macroscopic tumor stoves in liver,；In neoplasm in situ administration group, liver
Form is substantially intact, and at administration, tumor gets nowhere substantially.
The liver specimens of laboratory animal are placed in 10% formalin solution and fix 24～48 hours, paraffin embedding, section, he
Dyeing, makees pathological examination.Result is as shown in figure 9, after in-situ injection administration (a) in tumor, microsphere is in the tumor cell to surrounding
Cause obvious lethal effect, define obvious medicine and kill border, cancerous cell mortality in this region.Hepatic artery
Perfusion (b) is afterwards it is seen that the arteries of left side tumor region occur in that the thromboembolism that obvious microsphere and tissue fluid are formed, and here
The hepatoma carcinoma cell of areas adjacent occurs in that obvious death；Right side normal liver tissue region arteries equally occur in that microsphere and
The thromboembolism that tissue fluid is formed, also occurs in that damage in the part normal liver cell of this areas adjacent, but most of hepatocyte structure
Completely, form is normal.
4) the animal radioactivity monitoring of iodine 131 labelling chitosan-collagen complex microsphere
A. serum radioactivity monitoring
Postoperative 1st, 2,4,12 hour, 1,2,3,7,11,14,18,21,24,28,32,35 day, from rat femoral vein blood
0.1ml, measures gamma-ray and counts and calculate radioactivity in blood (cpm/g).Result is as shown in Figure 10, the blood of administration group in tumor
In liquid, free radioiodine 131 is more less than hepatic arterial infusion administration group, but after 7 days, in two groups of blood, free radioactivity is equal
It is reduced to background level.
B.spect/ct total body opacification
Postoperative 1st, 2,4,7,14,28,34 days, by the ge nm- of Huaxi Hospital Attached to Sichuan Univ Nuclear Medicine Department
Discovery670 carries out the spect/ct total body opacification of laboratory animal, and collection can peak be the characteristic peak 364kev of iodine 131, window width
15%, 1 times of amplification, matrix 128 × 128, front bit scan, acquisition time 2 minutes, result is as shown in figure 11.Each imaging
Using roi program, delineate liver, measure its radiocounting, and with the time as abscissa, ordinate value is calculated as follows: be (each
Time point liver counting-background count)/(liver counting-background count in first day), draw131The when m- radioactivity of i
(time-activity curve, t-a) curve.Count and draw t-a curve with the identical roi measurement each time point of thyroid.
Spect imaging prompting, all can be clearly seen microsphere injection rats'liver position in postoperative 34 days has radioactivity dense poly-.When
M- activity curve shows, As time goes on the radioactivity of liver region is gradually reduced, to when 28 days close to background, and
The radioactivity of thyroid gland areas is always maintained at reduced levels.
Experiment shows, after iodine isotope labelling chitosan-collagen complex microsphere implantation animal body is interior, can be colonized in implantation
Position；In the model of trans-hepatic artery interventional therapy rats'liver cancer in situ, can be good at being gathered in tumor locus.Two tests
Middle isotope iodide does not all stop in its hetero-organization for a long time.It is thus regarded that the chitosan-collagen complex microsphere of iodine isotope labelling
Treatment for entity tumor should be safely and effectively.
Experimental result illustrates, iodine isotope labelling chitosan-collagen complex microsphere of the present invention can be same with effectively treatment tumor
When spike excellent effect, can be used in clinical spike.
To sum up, chitosan-collagen complex microsphere of the present invention possess good biocompatibility, biodegradable, can stably tie
Close multiple radionuclides and medicine, and high with the combination rate of radioactive nuclide iodine, the iodine 131 labelling shitosan preparing-
Collagen composite microsphere is used for treatment and the spike excellent effect of tumor, and potential applicability in clinical practice is good.
Claims (17)
1. a kind of complex microsphere it is characterised in that: it is the microsphere being composited by shitosan and collagen protein.
2. microsphere according to claim 1 it is characterised in that: the mol ratio of described shitosan and collagen protein is 2:(1-
4).
3. microsphere according to claim 2 it is characterised in that: a diameter of 5～100 μm of described microsphere.
4. a kind of preparation method preparing microsphere described in claims 1 to 3 any one it is characterised in that: step is as follows:
(1) take shitosan and collagen protein, be prepared into solution；
(2) described for step (1) solution is made emulsion；
(3) the described emulsion of curing schedule (2), forms the microsphere of solidification；
(4) wash, separate the microsphere of solidification, you can.
5. preparation method according to claim 4 it is characterised in that: step is as follows: takes shitosan, adds containing collagen
In 2% acetic acid solution, according to shitosan and collagen mol ratio be 2:(1-4) ratio, by shitosan add solution in, stir
Mix and obtain water white transparency viscous solution；Aforementioned water white transparency viscous solution is added containing of 3.0～6.5 times of volumes of collagen solution
The liquid paraffin of sorbitol anhydride oleate, wherein, sorbitol anhydride oleate is 8:100 with the volume ratio of liquid paraffin, stirs
Mix and obtain emulsion liquid；To 25% glutaraldehyde of 0.045～0.126 times of volume of Deca collagen solution in emulsion under stirring
Solution crosslinking, makes microsphere solidified forming；Add isopropanol washing in products therefrom, the removal of impurity is gone in centrifugation；Products therefrom uses
Deionized water wash, and be filtered, be centrifuged, concentrate, you can.
6. purposes in the medicine preparing radiation treatment for the microsphere described in claims 1 to 3 any one.
7. a kind of Radiolabeled microsphere for radiation treatment it is characterised in that: it be marked with radionuclide right will
Seek the microsphere described in 1～3 any one.
8. Radiolabeled microsphere according to claim 7 it is characterised in that: described radionuclide is radioiodine.
9. Radiolabeled microsphere according to claim 7 it is characterised in that: described radioiodine is123i、124i、125I or131i.
10. the Radiolabeled microsphere according to claim 7～9 any one it is characterised in that: the mark of described radionuclide
Note rate is not less than 80%, preferably 81.27%～92.82%.
11. Radiolabeled microsphere according to claim 7～10 any one it is characterised in that: described Radiolabeled microsphere
Structure is as follows:
A kind of 12. preparation methoies preparing Radiolabeled microsphere described in claim 7～11 any one are it is characterised in that step
As follows:
Take the microsphere described in claim 1～3 any one, it is that 7.0pbs solution is swelling that every 50mg microsphere adds 1ml ph, then
Add 5mci131I nai, adding 50ul concentration is 20mg/ml chloramines-t, and room temperature magnetic force stirring reaction, after standing, adds partially
Sodium bisulfite stopped reaction；Centrifugation, abandons supernatant, gained labelling microsphere is carried out, lyophilizing, you can.
Purposes in the medicine of preparation treating cancer for the Radiolabeled microsphere described in 13. claim 7～11 any one.
14. purposes according to claim 13 it is characterised in that: described medicine be treatment hepatocarcinoma, renal carcinoma, breast carcinoma, first
Shape adenocarcinoma, the medicine of cancer of pancreas, gastrointestinal solid tumor or orthopaedics tumor.
Purposes in preparing neoplasm tracing agent for the Radiolabeled microsphere described in 15. claim 7～11 any one.
A kind of 16. pharmaceutical preparatioies for radiation treatment or spike it is characterised in that: it is with claim 7～11 times
One described Radiolabeled microsphere of meaning is active component, adds pharmaceutically acceptable adjuvant or complementary composition is prepared from
Preparation.
17. pharmaceutical preparatioies according to claim 16 it is characterised in that: described preparation be dried powder preparation, every milligram
Preparation contains 3 × 106～5 × 106Individual Radiolabeled microsphere.
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| CN111229139A (en) * | 2020-01-15 | 2020-06-05 | 四川大学华西医院 | Iodine 131-loaded collagen-polyvinyl alcohol embolism microsphere and preparation method thereof |
| CN114504661A (en) * | 2022-02-14 | 2022-05-17 | 四川大学华西医院 | 177 Lu-loaded degradable high polymer material microsphere and preparation method and application thereof |
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| CN111229139A (en) * | 2020-01-15 | 2020-06-05 | 四川大学华西医院 | Iodine 131-loaded collagen-polyvinyl alcohol embolism microsphere and preparation method thereof |
| CN111229139B (en) * | 2020-01-15 | 2020-11-24 | 四川大学华西医院 | Iodine 131-loaded collagen-polyvinyl alcohol embolism microsphere and preparation method thereof |
| CN115038467A (en) * | 2020-01-30 | 2022-09-09 | 凯生物技术株式会社 | Method for preparing chitosan hydrogel-chelating agent for treating cancer |
| CN114522256A (en) * | 2021-12-27 | 2022-05-24 | 中山大学附属第五医院 | Polyhydroxyalkanoate drug-loaded radiotherapy microspheres and preparation method and application thereof |
| CN114522256B (en) * | 2021-12-27 | 2023-09-08 | 中山大学附属第五医院 | Polyhydroxyalkanoate drug-loaded radiotherapy microsphere and preparation method and application thereof |
| CN114504661A (en) * | 2022-02-14 | 2022-05-17 | 四川大学华西医院 | 177 Lu-loaded degradable high polymer material microsphere and preparation method and application thereof |
| CN114949269A (en) * | 2022-05-10 | 2022-08-30 | 苏州大学 | Gel microsphere preparation, preparation method, medicine box and application in preparation of radioactive gel microspheres |
| CN114949269B (en) * | 2022-05-10 | 2023-08-04 | 苏州大学 | Gel microsphere preparation, preparation method, medicine box and application thereof in preparation of radioactive gel microspheres |
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