CN100502881C - Degradable polymer supported nanometer daunorubicin microsphere and its preparation process - Google Patents
Degradable polymer supported nanometer daunorubicin microsphere and its preparation process Download PDFInfo
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- CN100502881C CN100502881C CNB2006101253671A CN200610125367A CN100502881C CN 100502881 C CN100502881 C CN 100502881C CN B2006101253671 A CNB2006101253671 A CN B2006101253671A CN 200610125367 A CN200610125367 A CN 200610125367A CN 100502881 C CN100502881 C CN 100502881C
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Abstract
The present invention is degradable polymer supported nanometer Daunorubicin microsphere and its preparation process. The microsphere has size of 200-800 nm, Daunorubicin carrying rate of 3.05-18.4 %, encapsulating rate of 53.2-88.3 %, and degradable polymer polylactic acid or polylactic acid-polyglycolic acid copolymer. Experiment shows that the nanometer Daunorubicin microsphere may be released continuously in buffering phosphate solution for 2-8 weeks and the releasing rate and period may be controlled through changing the sort and molecular weight of the polymer. The nanometer Daunorubicin microsphere is superior to conventional Daunorubicin preparation, and has higher acute promyelocytic leukemia cell ingesting efficiency, higher tumor cell inhibiting rate and long effective period.
Description
Technical field
The invention belongs to field of biomedical materials, be specifically related to degradable polymer supported nanometer Daunorubicin microsphere and preparation method thereof.
Background technology
Daunorubicin (Daunorubicin, DNR) be that a class is extensive use of clinically and reaches the anthracycline antibiotics with broad-spectrum high efficacy active anticancer in more than 30 year, be mainly used in the treatment acute myeloblastic leukemia, multiple blood tumor and solid tumor are also had significant curative effect.DNR can change the dna molecular conformation with in its structural aromatic rings intercalation of DNA chain, suppresses duplicating of DNA and synthesizing of RNA, mediates living radical simultaneously under aerobic conditions, as ultra-oxygen anion free radical (O
2-) and hydroxyl radical free radical (OH-), cause and the lipid peroxidation of cell mitochondrial film and endoplasmic reticulum cause cytotoxicity; But DNR also can with mitochondrial DNA, particularly with cuorin DNA specific bond, cause cardiac toxicity thereby the complex of generation can suppress the activity of respiratory enzyme.
Daunorubicin by drug administration by injection, because its half-life is shorter, can not play one's part to the full in clinical practice.Its untoward reaction mainly is bone marrow depression reaction and cardiac toxicity.Bone marrow depression is a modal toxic reaction in the cancer therapy drug, sees so that leukocytic minimizing more, and be thrombocytopenia secondly, still there is not the effectively method of preventing and treating at present.Studies show that, though anthracene nucleus medicament between the intercalation of DNA chain and its active anticancer confidential relation being arranged, drug molecule combines the basis that its toxic and side effects often produces with the low specificity of DNA.Simultaneously, anthracene nucleus medicament is done a large amount of free radicals that the time spent produces have also caused the body myocardial cell when forming cytotoxicity damage, causes the cardiac toxicity reaction, and this is that anthracene nucleus medicament is peculiar basically.Secondly, daunorubicin also is easy to induce celliferous drug resistance again, is considered to the most representative cytotoxic drug in the multidrug resistance tumor cells drug resistance spectrum.
Chemotherapy, radiotherapy and operation are three big conventional treatments of treatment malignant tumor, and the quality of life that has improved patient has to a certain extent prolonged life cycle.But general radiation and chemotherapy lacks selectivity, and also injuring normal cell when suppressing tumor causes untoward reaction, and operative treatment brings various wounds and complication to patient, and the completeness of operation also has problems.Therefore adopt Nano medication to carry out oncotherapy now and become the research focus.At present, the external existing daunorubicin liposome medicine that obtains FDA approval use
, people such as domestic Ma Jie have also invented a kind of daunorubicin hydrochloride lipidosome injection, also have the human magnetic nano-particle to treat leukemia as the daunorubicin carrier.
Summary of the invention
The preparation method that the purpose of this invention is to provide a kind of degradable nanometer Daunorubicin microsphere based on double-deck emulsion-solvent evaporates theory, short at the daunorubicin half-life, side effect such as toxicity is big, by daunorubicin being wrapped in degradable polymer (polylactic acid, polylactic acid-co-glycolic acid) makes Nano microsphere in, thereby prolong daunorubicin stop and action time in vivo, reduce the use amount and the access times of daunorubicin, thereby improve the ratio that daunorubicin is organized with cellular uptake and reduce its toxic and side effects, can strengthen simultaneously the targeting effect of medicine again, and then lay the foundation for all kinds of researchs and the clinical practice of daunorubicin.
A kind of nanometer Daunorubicin medicine microspheres of the present invention is the degradable polymer supported daunorubicin microsphere of nanoscale, particle diameter is between 200-800 nanometers, carry daunorubicin medicine rate 3.05%～18.4%, envelop rate is 53.2%～88.3%, and described degradable polymer is polylactic acid or polylactic acid-co-glycolic acid.
The preparation method of nanometer Daunorubicin medicine microspheres of the present invention is characterized in that double-deck emulsion-solvent evaporation method, and its preparation process is as follows:
Step 1, according to the theoretical carrying drug ratio of the polymer supported nanometer Daunorubicin microsphere that will prepare, make mixed organic solvents with dichloromethane and acetone, the preparation PLA concentration is 5-20 mg/ml organic solutions, perhaps polylactic acid-co-glycolic acid concentration is 5-25 mg/ml organic solutions, and described mixed organic solvents volume ratio is a dichloromethane: acetone=3-5:1;
Step 2, be 2.5-10 mg/ml daunorubicin aqueous solutions, and it is fully dissolved with the deionized water compound concentration;
Dichloromethane/acetone the organic solution of step 3, polylactic acid that step 1 is prepared, the perhaps dichloromethane of polylactic acid-co-glycolic acid/acetone organic solution, the daunorubicin aqueous solution of step 2 preparation is according to organic solution: aqueous solution volume ratio=5-20:1 mixes, and adding emulsifying agent soil temperature 80, perhaps sorbester p17, adopt the method for ultrasonic or homogenizing to carry out emulsifying, get colostric fluid;
Step 4, the colostric fluid of step 3 is expelled to contain dispersant gelatin or polyvinyl alcohol concentration be 0.5%-1% aqueous phase, adopts the method for ultrasonic or homogenizing to carry out emulsifying again, double emulsion;
Step 5, the double emulsion that step 4 is obtained are added dropwise to slowly that to contain dispersant gelatin or polyvinyl alcohol concentration be 0.5%-1% aqueous phase, this process is carried out under the high-speed stirred state, after double emulsion drips, under atmospheric pressure state, keep and stir more than 1 hour, and then under negative pressure state, keep stirring, make the organic solvent volatilization fully;
Step 6, the material after step 5 finished take out, by the solidified degradable polymer supported nanometer Daunorubicin microsphere of the centrifugal collection of low-temperature and high-speed, and, promptly obtain polylactic acid or polylactic acid-co-glycolic acid supported nanometer Daunorubicin microsphere with 2-4 postlyophilization of distilled water cleaning.
The present invention adopts double-deck emulsion-solvent evaporates technology to prepare the discharged Nano microsphere of water solublity antitumor drug daunorubicin, from stereoscan photograph (accompanying drawing 1,2) as can be seen, thus obtained microsphere all has the surface of very regular sphere and smoother, and good dispersion, particle diameter is all at nanoscale.Extracorporeal releasing experiment shows that the prepared degradable polymer supported nanometer Daunorubicin microsphere of the present invention can continue to discharge 2-8 week, and can come sustained release speed and deenergized period according to type of polymer and molecular weight thereof in phosphate buffered solution.The cellular uptake experiment shows that the prepared degradable polymer supported nanometer Daunorubicin microsphere of the present invention has higher ingestion efficiency to the more conventional daunorubicin medicine of acute promyelocytic leukemic (HL-60) cell.Cytotoxicity experiment shows, the prepared degradable polymer supported nanometer Daunorubicin microsphere of the present invention is to the more conventional daunorubicin medicine of the suppression ratio of tumor cell viability height, and action time is longer.In the tumor intervention therapeutic to mice, the venous thrombosis therapeutic effect of the degradable polymer supported nanometer Daunorubicin microsphere that the present invention is prepared is better than conventional administration, and the tumor propagation rate obtains obvious suppression.
Degradable polymer supported nanometer Daunorubicin microsphere of the present invention is used for oncotherapy.Compare liposome, the parcel efficient of solid polymer Nano microsphere is higher, and stability is better, and the phenomenon that water soluble drug oozes out fast can not occur in blood circulation.Simultaneously, than magnetic nano-particle, avoided that the magnetic skewness of magnetic particle is even to be difficult to remove defectives such as causing long-term toxic and side effects and needing no foreign introduction by magnetic field in body.By using the degradable polymer material that daunorubicin is wrapped up, can prolong its effective acting time in vivo, improve drug effect, reduce cellulotoxic side effect simultaneously, avoid cardiac toxicity.And can be with this nano controlled release medicinal application in the tumor interventional therapy, utilize the permeability enhancing of tumor tissues drug targeting to be reduced Normocellular influence in tumor cell with delay (EPR) effect, can also reduce simultaneously the generation of multidrug resistance, therefore the degradable nanometer Daunorubicin microsphere of this method invention has the scope of application widely, can significantly improve the therapeutic quality of conventional treatments.
Description of drawings
Fig. 1. the stereoscan photograph of the polylactic acid supported nanometer Daunorubicin microsphere of embodiment 4 preparations
Fig. 2. the stereoscan photograph of the polylactic acid-co-glycolic acid supported nanometer Daunorubicin microsphere of embodiment 7 preparations
The specific embodiment
Below by instantiation the present invention is done further explaination.The % of aqueous gelatin solution represents to contain in 100 milliliters of the solution gram number of gelatin among the following embodiment, and the % of polyvinyl alcohol water solution represents to contain in 100 milliliters of the solution gram number of polyvinyl alcohol.
Embodiment 1
With the polylactic acid volume ratio is that the organic solvent dissolution of dichloromethane: acetone=3:1 is made into the organic solution that concentration is 5 mg/ml, mix for 5:1 by volume with the aqueous solution that contains daunorubicin 2.5 mg/ml again, with ultransonic method emulsifying is colostric fluid, this colostric fluid joined in 30 milliliter 1% the aqueous gelatin solution, ultrasonic emulsification forms double emulsion once more, double emulsion slowly is added dropwise in 150 milliliter 0.5% the aqueous gelatin solution, keep high-speed stirred during dropping, keep stirring 1 hour after dripping end, the Nano microsphere surface portion is solidified, and then under negative pressure state, keep stirring, make the organic solvent in the emulsion system quicken to evaporate into fully by suction function, clean postlyophilizations acquisition polylactic acid supported nanometer Daunorubicin microsphere product three times at last by the centrifugal collection solid nano of low-temperature and high-speed microsphere, and with distilled water.
Laser particle size analysis shows that the gained nanoparticle is that effective diameter is normal distribution with 387 nanometers, and polydispersity is 0.268.Scanning electron microscope is observed this Nano microsphere down and is had regular spherical design, good dispersion in emulsion.Measurement result: carrying the daunorubicin amount is quality 3.05%, and envelop rate is 53.2%.
Embodiment 2
With the polylactic acid volume ratio is that the organic solvent dissolution of dichloromethane: acetone=4:1 is made into the organic solution that concentration is 10 mg/ml, mix for 10:1 by volume with the aqueous solution that contains daunorubicin 5 mg/ml again, with ultransonic method emulsifying is colostric fluid, this colostric fluid joined in 30 milliliter 1% the aqueous gelatin solution, ultrasonic emulsification forms double emulsion once more, double emulsion slowly is added dropwise in 150 milliliter 0.5% the aqueous gelatin solution, keep high-speed stirred during dropping, keep stirring 2 hours after dripping end, the Nano microsphere surface portion is solidified, and then under negative pressure state, keep stirring, make the organic solvent in the emulsion system quicken to evaporate into fully by suction function, clean postlyophilizations acquisition polylactic acid supported nanometer Daunorubicin microsphere product three times at last by the centrifugal collection solid nano of low-temperature and high-speed microsphere, and with distilled water.
Laser particle size analysis shows that the gained Nano microsphere is that effective diameter is normal distribution with 495 nanometers, and polydispersity is 0.161.Scanning electron microscope is observed this Nano microsphere down and is had regular spherical design, good dispersion in emulsion.Measurement result: carrying the daunorubicin amount is quality 3.52%, and envelop rate is 59.3%.
Embodiment 3
With the polylactic acid volume ratio is that the organic solvent dissolution of dichloromethane: acetone=5:1 is made into the organic solution that concentration is 20 mg/ml, mix for 20:1 by volume with the aqueous solution that contains daunorubicin 10 mg/ml again, with ultransonic method emulsifying is colostric fluid, this colostric fluid joined in 30 milliliter 1% the aqueous gelatin solution, ultrasonic emulsification forms double emulsion once more, double emulsion slowly is added dropwise in 150 milliliter 0.5% the aqueous gelatin solution, keep high-speed stirred during dropping, keep stirring 1.5 hours after dripping end, the Nano microsphere surface portion is solidified, and then under negative pressure state, keep stirring, make the organic solvent in the emulsion system quicken to evaporate into fully by suction function, clean postlyophilizations acquisition polylactic acid supported nanometer Daunorubicin microsphere product three times at last by the centrifugal collection solid nano of low-temperature and high-speed microsphere, and with distilled water.
Laser particle size analysis shows that the gained Nano microsphere is that effective diameter is normal distribution with 735 nanometers, and polydispersity is 0.128.Scanning electron microscope is observed this Nano microsphere down and is had regular spherical design, good dispersion in emulsion.Measurement result: carrying the daunorubicin amount is quality 5.92%, and envelop rate is 51.3%.
Embodiment 4
With the polylactic acid volume ratio is that the organic solvent dissolution of dichloromethane: acetone=4:1 is made into the organic solution that concentration is 10 mg/ml, mix for 10:1 by volume with the aqueous solution that contains daunorubicin 5 mg/ml again, method emulsifying with homogenizing is colostric fluid, this colostric fluid joined in 30 milliliter 0.5% the polyvinyl alcohol water solution, emulsifying forms double emulsion once more, double emulsion slowly is added dropwise in 150 milliliter 1% the polyvinyl alcohol water solution, keep high-speed stirred during dropping, keep stirring 2 hours after dripping end, the Nano microsphere surface portion is solidified, and then under negative pressure state, keep stirring, make the organic solvent in the emulsion system quicken to evaporate into fully by suction function, clean postlyophilizations acquisition polylactic acid supported nanometer Daunorubicin microsphere product three times at last by the centrifugal collection solid nano of low-temperature and high-speed microsphere, and with distilled water.
Laser particle size analysis shows that the gained Nano microsphere is that effective diameter is normal distribution with 287 nanometers, and polydispersity is 0.118.Scanning electron microscope is observed this Nano microsphere down and is had regular spherical design, good dispersion in emulsion.Measurement result: carrying the daunorubicin amount is quality 12.5%, and envelop rate is 79.8%.
Embodiment 5
With polylactic acid-co-glycolic acid volume ratio is that the organic solvent dissolution of dichloromethane: acetone=3:1 is made into the organic solution that concentration is 5 mg/ml, mix for 5:1 by volume with the aqueous solution that contains daunorubicin 2.5 mg/ml again, method emulsifying with homogenizing is colostric fluid, this colostric fluid joined in 30 milliliter 1% the polyvinyl alcohol water solution, emulsifying forms double emulsion once more, double emulsion slowly is added dropwise in 150 milliliter 0.5% the polyvinyl alcohol water solution, keep high-speed stirred during dropping, keep stirring 1 hour after dripping end, the Nano microsphere surface portion is solidified, and then under negative pressure state, keep stirring, make the organic solvent in the emulsion system quicken to evaporate into fully by suction function, clean postlyophilizations acquisition polylactic acid supported nanometer Daunorubicin microsphere product three times at last by the centrifugal collection solid nano of low-temperature and high-speed microsphere, and with distilled water.
Laser particle size analysis shows that the gained Nano microsphere is that effective diameter is normal distribution with 315 nanometers, and polydispersity is 0.126.Scanning electron microscope is observed this Nano microsphere down and is had regular spherical design, good dispersion in emulsion.Measurement result: carrying the daunorubicin amount is quality 6.59%, and envelop rate is 61.5%.
Embodiment 6
With polylactic acid-co-glycolic acid volume ratio is that the organic solvent dissolution of dichloromethane: acetone=4:1 is made into the organic solution that concentration is 15 mg/ml, mix for 10:1 by volume with the aqueous solution that contains daunorubicin 5 mg/ml again, method emulsifying with homogenizing is colostric fluid, this colostric fluid joined in 30 milliliter 1% the polyvinyl alcohol water solution, emulsifying forms double emulsion once more, double emulsion slowly is added dropwise in 150 milliliter 0.5% the polyvinyl alcohol water solution, keep high-speed stirred during dropping, keep stirring 2 hours after dripping end, the Nano microsphere surface portion is solidified, and then under negative pressure state, keep stirring, make the organic solvent in the emulsion system quicken to evaporate into fully by suction function, clean postlyophilizations acquisition polylactic acid supported nanometer Daunorubicin microsphere product three times at last by the centrifugal collection solid nano of low-temperature and high-speed microsphere, and with distilled water.
Laser particle size analysis shows that the gained Nano microsphere is that effective diameter is normal distribution with 352 nanometers, and polydispersity is 0.303.Scanning electron microscope is observed this Nano microsphere down and is had regular spherical design, good dispersion in emulsion.Measurement result: carrying the daunorubicin amount is quality 13.6%, and envelop rate is 80.5%.
Embodiment 7
With polylactic acid-co-glycolic acid volume ratio is that the organic solvent dissolution of dichloromethane: acetone=5:1 is made into the organic solution that concentration is 25 mg/ml, mix for 20:1 by volume with the aqueous solution that contains daunorubicin 10 mg/ml again, method emulsifying with homogenizing is colostric fluid, this colostric fluid joined in 30 milliliter 1% the polyvinyl alcohol water solution, emulsifying forms double emulsion once more, double emulsion slowly is added dropwise in 150 milliliter 0.5% the polyvinyl alcohol water solution, keep high-speed stirred during dropping, keep stirring 1.5 hours after dripping end, the Nano microsphere surface portion is solidified, and then under negative pressure state, keep stirring, make the organic solvent in the emulsion system quicken to evaporate into fully by suction function, clean postlyophilizations acquisition polylactic acid supported nanometer Daunorubicin microsphere product three times at last by the centrifugal collection solid nano of low-temperature and high-speed microsphere, and with distilled water.
Laser particle size analysis shows that the gained Nano microsphere is that effective diameter is normal distribution with 436 nanometers, and polydispersity is 0.326.Scanning electron microscope is observed this Nano microsphere down and is had regular spherical design, good dispersion in emulsion.Measurement result: carrying the daunorubicin amount is quality 18.4%, and envelop rate is 88.3%.
Embodiment 8
With polylactic acid-co-glycolic acid volume ratio is that the organic solvent dissolution of dichloromethane: acetone=4:1 is made into the organic solution that concentration is 10 mg/ml, mix for 10:1 by volume with the aqueous solution that contains daunorubicin 5 mg/ml again, with ultransonic method emulsifying is colostric fluid, this colostric fluid joined in 30 milliliter 0.5% the aqueous gelatin solution, ultrasonic emulsification forms double emulsion once more, double emulsion slowly is added dropwise in 150 milliliter 1% the aqueous gelatin solution, keep high-speed stirred during dropping, keep stirring 2 hours after dripping end, the Nano microsphere surface portion is solidified, and then under negative pressure state, keep stirring, make the organic solvent in the emulsion system quicken to evaporate into fully by suction function, clean postlyophilizations acquisition polylactic acid supported nanometer Daunorubicin microsphere product three times at last by the centrifugal collection solid nano of low-temperature and high-speed microsphere, and with distilled water.
Laser particle size analysis shows that the gained Nano microsphere is that effective diameter is normal distribution with 643 nanometers, and polydispersity is 0.205.Scanning electron microscope is observed this Nano microsphere down and is had regular spherical design, good dispersion in emulsion.Measurement result: carrying the daunorubicin amount is quality 6.5%, and envelop rate is 68.3%.
Embodiment 9
Acute promyelocytic leukemic (HL-60) cell is tested the picked-up of polylactic acid-co-glycolic acid supported nanometer Daunorubicin microsphere:
(1) transferring the HL-60 cell concentration is 1 * 106/ml, adds 24 orifice plates, every hole 1ml;
(2) certain density pure DNR solution and DNR-NP suspension are joined in the culture plate, behind the cultivation certain hour, respectively at five time points (30min, 60min, 90min, 120min, 180min) taking-up cell;
(3) 4 ℃ of centrifugal 5min of 1000rpm, collecting cell, the culture medium RPMI1640 with increase serum washes 2 times then;
(4) contain E.C. 3.4.21.64 and the 1%SDS solution dissolved cell of 50 μ g/ml with 1.5ml, 37 ℃ of continuous oscillation 12 hours;
(5) cell extraction liquid is collected by the centrifugal 10min of 3000rpm;
(6) fluorescence intensity of usefulness fluorescence spectrophotometer measurement extract;
(7) calculate content of dispersion in the cell by the fluorescence intensity standard curve.
The result shows, HL-60 cell surpasses 30% to the ingestion efficiency of polylactic acid-co-glycolic acid supported nanometer Daunorubicin microsphere, and HL-60 cell to the ingestion efficiency of conventional daunorubicin administration only less than 15%.
Claims (2)
1, a kind of nanometer Daunorubicin medicine microspheres, it is characterized in that described nanometer Daunorubicin medicine microspheres is the degradable polymer supported daunorubicin microsphere of nanoscale, particle diameter is between 200-800 nanometers, carry daunorubicin medicine rate 3.05%～18.4%, envelop rate is 53.2%～88.3%, and described degradable polymer is polylactic acid-co-glycolic acid.
2, the preparation method of the described nanometer Daunorubicin medicine microspheres of claim 1 is characterized in that preparation method is double-deck emulsion-solvent evaporation method, and its preparation process is as follows:
Step 1, according to the theoretical carrying drug ratio of the polymer supported nanometer Daunorubicin microsphere that will prepare, make mixed organic solvents with dichloromethane and acetone, preparation polylactic acid-co-glycolic acid concentration is 5-25 mg/ml organic solutions, and described mixed organic solvents volume ratio is a dichloromethane: acetone=3-5:1;
Step 2, be 2.5-10 mg/ml daunorubicin aqueous solutions, and it is fully dissolved with the deionized water compound concentration;
Dichloromethane/acetone the organic solution of step 3, polylactic acid-co-glycolic acid that step 1 is prepared, daunorubicin aqueous solution with step 2 preparation, according to its organic solution: aqueous solution volume ratio=5-20:1 mixes, and adding emulsifying agent soil temperature 80, perhaps sorbester p17, adopt the method for ultrasonic or homogenizing to carry out emulsifying, get colostric fluid;
Step 4, the colostric fluid that step 3 is obtained are expelled to that to contain dispersant gelatin or polyvinyl alcohol concentration be 0.5%-1% aqueous phase, adopt the method for ultrasonic or homogenizing to carry out emulsifying again, double emulsion;
Step 5, the double emulsion that step 4 is obtained are added dropwise to slowly that to contain dispersant gelatin or polyvinyl alcohol concentration be 0.5%-1% aqueous phase, this process is carried out under the high-speed stirred state, after double emulsion drips, under atmospheric pressure state, keep and stir more than 1 hour, and then under negative pressure state, keep stirring, make the organic solvent volatilization fully;
Step 6, the material after step 5 finished take out, by the solidified degradable polymer supported nanometer Daunorubicin microsphere of the centrifugal collection of low-temperature and high-speed, and, promptly obtain polylactic acid-co-glycolic acid supported nanometer Daunorubicin microsphere with 2-4 postlyophilization of distilled water cleaning.
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| 聚乳酸载柔红霉素纳米微球的制备. 曹瑞锐，张胜民，童强松等.中国生物医学工程学会第六次会员代表大会暨学术会议论文摘要汇编. 2004 |
| 聚乳酸载柔红霉素纳米微球的制备. 曹瑞锐，张胜民，童强松等.中国生物医学工程学会第六次会员代表大会暨学术会议论文摘要汇编. 2004 * |
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