聚乳酸卡氮芥载体研究
摘要
卡氮芥是一种有效治疗恶性神经胶质瘤的药物，临床疗效显著，是目前脑瘤治疗的首选药物。但半衰期短，难溶于水，毒副作用大。为克服上述缺点，本文采用溶剂挥发法制备了抗癌药物BCNU的聚乳酸微球。
用扫描电子显微镜（SEM），光学显微镜观察其表面形态，显色法测定微球载药率，考察了不同制备条件对微球的粒径和形态，载药率，包封率等性能的影响。可观察到所制备载药微球表面光滑圆整，粒径分布均匀。结合SEM分析，微球粒径受油相分散方式和聚乳酸分子量的影响显著。载药率可达15％左右，药物包封率可达40％左右。
用差热扫描分析（DSC）对载药微球中药物分布状态及稳定性进行测定：BCNU在PLA基质中以分子状态存在，其药物稳定性有所下降。载药微球体外释放试验显示聚乳酸分子量、药物含量、微球粒径对PLA-BCNU微球释放有不同程度的影响。微球释药时间长，可持续释放70天左右，释药速率较稳定，符合Higuchi时间平方根模型。提高微球表面光滑度可适当减小药物突释程度和时间。SEM观察水解后聚乳酸微球，其骨架仍然存在，但球形较不规则，表面出现一些凹凸不平，这与聚乳酸微球自身的降解和药物的溶出有关。
并对PLA和PLA/PEG共混两种载药膜片的释放、降解行为作出比较。PLA在加入PEG后，其药物释放速率和本身降解速率明显加快，可进一步改善PLA释药特性。
BCNU, relatively high lipid solubility and low molecular weight, is widely used for the treatment of malignant gliomas. However, BCNU is limited by its systemic toxicity and characteristic, such as its water-insolution and short half life. In order to solve these problems, the following work has been done in this dissertation.
PLA-BCNU microspheres(MPs) were prepared by Solvent evaporation process via using PLA as the polymer matrix. Through SEM(Scanning electronic microscope) micrograph, the microspheres sizes and standard deviation were effected by molecular weight and oil-phase distribution models. Smooth surface without cavities or crystal of the drug could be get in this dissertation.
Colorimetric method was used to determinate drug loaded ratio and drug encapsulation efficiency of MPs, and they could reach 15% and 40%, respectively.
BCNU dispersion and stability in the MPs was studied by DSC(Differential scanning calorimetry analyses).
The in vitro release experiments studied the effects of molecular weight of PLA, drug content in MPs and MPs sizes on release behavior of microspheres. The release BCNU microspheres was slow(>70day) and stable, and could be described as square root-time process. Improve the surfaces of MPs could weaken their degree of burst release. Some degradation of MPs after releasing for 1 month could be seen by SEM. The basic sphericity was remained but with some cavities which were the channels for BCNU when delivered into the environment.
Addition of PEG to PLA film can improve release behavior of PLA-BCNU carrier by increasing the speed of drug release.
用扫描电子显微镜（SEM），光学显微镜观察其表面形态，显色法测定微球载药率，考察了不同制备条件对微球的粒径和形态，载药率，包封率等性能的影响。可观察到所制备载药微球表面光滑圆整，粒径分布均匀。结合SEM分析，微球粒径受油相分散方式和聚乳酸分子量的影响显著。载药率可达15％左右，药物包封率可达40％左右。
用差热扫描分析（DSC）对载药微球中药物分布状态及稳定性进行测定：BCNU在PLA基质中以分子状态存在，其药物稳定性有所下降。载药微球体外释放试验显示聚乳酸分子量、药物含量、微球粒径对PLA-BCNU微球释放有不同程度的影响。微球释药时间长，可持续释放70天左右，释药速率较稳定，符合Higuchi时间平方根模型。提高微球表面光滑度可适当减小药物突释程度和时间。SEM观察水解后聚乳酸微球，其骨架仍然存在，但球形较不规则，表面出现一些凹凸不平，这与聚乳酸微球自身的降解和药物的溶出有关。
并对PLA和PLA/PEG共混两种载药膜片的释放、降解行为作出比较。PLA在加入PEG后，其药物释放速率和本身降解速率明显加快，可进一步改善PLA释药特性。
BCNU, relatively high lipid solubility and low molecular weight, is widely used for the treatment of malignant gliomas. However, BCNU is limited by its systemic toxicity and characteristic, such as its water-insolution and short half life. In order to solve these problems, the following work has been done in this dissertation.
PLA-BCNU microspheres(MPs) were prepared by Solvent evaporation process via using PLA as the polymer matrix. Through SEM(Scanning electronic microscope) micrograph, the microspheres sizes and standard deviation were effected by molecular weight and oil-phase distribution models. Smooth surface without cavities or crystal of the drug could be get in this dissertation.
Colorimetric method was used to determinate drug loaded ratio and drug encapsulation efficiency of MPs, and they could reach 15% and 40%, respectively.
BCNU dispersion and stability in the MPs was studied by DSC(Differential scanning calorimetry analyses).
The in vitro release experiments studied the effects of molecular weight of PLA, drug content in MPs and MPs sizes on release behavior of microspheres. The release BCNU microspheres was slow(>70day) and stable, and could be described as square root-time process. Improve the surfaces of MPs could weaken their degree of burst release. Some degradation of MPs after releasing for 1 month could be seen by SEM. The basic sphericity was remained but with some cavities which were the channels for BCNU when delivered into the environment.
Addition of PEG to PLA film can improve release behavior of PLA-BCNU carrier by increasing the speed of drug release.
引文
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[2]肖延龄，李伯，载药纳米微粒的临床应用研究进展，国外医学生物医学工程分册，2002，25：174~177
[3]平其能主编，现代药剂学，北京：中国医药科技出版社，1998，638～645
[4]俞耀庭，张兴栋，生物医用材料，天津：天津大学出版社，2000,102~120
[5]L.B, Peppas, Recent advances on the use of biodegradable microparticles and nanoparticles the controlled drug delivery, Int.J.PHarm 1995, 116:1～9
[6]Kumaresh S, Tejraj M, Biodegradable polymeric nanoparticles as drug delivery devices, Journal of Controlled Release, 2001, 70:1～20
[7]陆彬,药物新剂型与新技术,北京：人民卫生出版,1998,57～72
[8] I. Bertoti, Biodegradable polymeric nanoparticles as drug delivery devices, J. of Controlled Release，2001，70: 1～20
[9] 张立德，牟季美.，纳米材料和纳米结构，北京：科学出版社，2001,58~63
[10] E. Kiss, I. Bertoti. XPS and wettability characterization of modified poly(lactic acid) and poly(lactic/glycolic acid) films. J. of Colloid and Interface Sci. 2002, 245: 91~98
[11] James M. Anderson, Matthew S. Shive. Biodegradation and biocompatibility of PLA and PLGA microspheres, Advanced Drug Delivery Rev. 1997, 28:5~24
[12]Parney IF, Hao C, Ppetruk KC. Glioma immunology and immunotherapy. Neurosurgery, 2000,46:778～792
[13]Rutka JT, Taylor M, Mainprize T, et al. Molecular biology and neurosurgery in the third millennium, Neurosurgery, 2000,46(5) :1034～1051
[14]Lees, K.R. Advances in neuroprotection trials, Eur.Neurol. 2000,45:6～10
[15]Dawson, D.A. et al. A comparative assessment of the efficacy and side-effect liability of neuroprotective compounds inexperimental stroke. Brain Res. 2001,892:344～350
[16]P. Couvreur, L. Grislain ,Biodegradable polymeric nanoparticles and drug carriers for antitumor agents, Polymeric Nanoparticles and Microspheres, CRC Press, Boca Raton, FL, 1986: 27～93
[17]J. Kreuter, R.N, Alyautdin, D.A, Passage of peptides through the blood–brain barrier with colloidal polymer particles (nanoparticles), Brain Res, 1995 ,674: 171～174
[18]M.A.Spear, U. Herrlinger, N.Rainov,P. Pechan, R.Weissleder, X.O. Breakefield,
Targeting gene therapy to CNS malignancies, J.Neurol.Virol.1998
[19]Gutin PH, Posner JB. Neuro-oncology: Diaynosis and management of cerebral glioma-past, present, and future, Neurosurgery, 2000,47(1): 1～8
[20]Robert L. Gutman et al. Targeted drug delivery for brain cancer treatment. Journal of Controlled Release, 2000,(65):31～41
[21]Vladimir P. Torchilin,ET, Structure and design of polymeric surfactant-based drug delivery systems,J. of Controlled Release 2001, 73: 137～172
[22]M.T. Peracchia, E. Fatta, Stealth PEGylated polycyanoacrylate nanoparticles for travenous administration and splenic targeting, J. of Controlled Release 1999,60: 121～128
[23]万东华,周建平.穿透血脑屏障的药物传递系统研究近况.药学进展,2001,25(5):260-265.
[24]B. Zlokovich,The in vivo approaches for studying peptide interaction at the blood－brain barrier, Peptides, 1989,10:249～254
[25]Kazunori Kataoka , Atsushi Harada , Block copolymer micelles for drug delivery: design,characterization and biological significance ，Advanced Drug Delivery Reviews，2001, 47: 113～131
[26]K.E. Uhrich, S. M. Cannizzaro, Polymeric systems for controlled drug release, Chem.Rev. 1999, 99: 3181～3198
[27]Lambert G,Fattal E,Couvreur P, Nanoparticles systems for the delivery of antisense oligonucleotides ,Adv. Drug Deliv. Rev.,2001,47:99～112.
[28]J?rg Kreuter, Nanoparticulate systems for brain delivery of drugs, AdvancedDrug Delivery Reviews, 2001,47:65～81
[29] Li, J.T, Caldwell, K. D, Plasma protein interactions with Pluronic treated colloids, Colloids Surfaces B-Biointerfaces1997, 7: 9～22
[30]汪锡安，胡宁先编译,医用高分子,上海：上海科学技术文献出版社，1992,137～168
[31]平其能，中国新药杂志，纳米药物和纳米载体系统，2002，11（1）：42～46
[32]Kreuter J, Nanoparticles and microparticles for drug and vaccine delivery,J.Anat.,1996,189(12):503.
[33]Radwan MA, Zaghloul LY,Aly ZH, In vivo performance of parenteral theophylline-loaded polyisobutylcyanoacrylate nanoparticles in rats, Eur. J.Pharm.Sci.,1999,8(2):95～99
[34] 郭健新，王荣，以聚乳酸为聚合物材料制备微粒给药系统，药学进展，1996，
20(3):135~138
[35]Yoshiaka Kaw, Hiromistu Yama. Properties of a peptide containing DL-lactide/glycolide copolymer nanosphere by novel emulsion solvent diffusion method, Europe J. of Pharmaceutical and Biopharmaceutical, 1998, 5: 41~43
[36]Patrick B., O’Donnell, James, Preparation of microspheres by the solvent evaporation technique, Advanced Drug Delivery Reviews, 1997, 28: 25~26
[37] T. Govender, T. Riley. Defining the drug incorporation properties of PLA-PEG nanoparticles, Int. J. of Pharmaceutics, 2000, 199: 95~97.
[38]H. Jeffery, S. S. Davis, The preparation and characterization of poly( lactide-co-glycolide) microparticles: oil-in-water emulsion solvent evaporation, Int. J. PHarm. 1991,77: 41～51
[39]R.K.Jain, Delivery of molecular and cellular medicine to solid tumors, J.Control.Rel.
[40] A. Rothen-Weinholda, K. Besseghirc, E. Vuaridel. Injection-molding versus extrusion as manufacturing technique for the preparation of biodegradable implants. European J. of Pharmaceutics and Biopharmaceutics, 1999, 48:113~121
[41] C. Konig, K. Rufeux, E. Wintermantel, Auto sterilization of biodegradable implants by injection molding process. J. Biomed. Mater. Res., 1997, 38:115~119.
[42] Guilford Pharmaceuticals Inc.GLIADEL WAFER . U.S：Patent Nos. 4,789,724 and 5,179,189.
[43] M.L. Hans, A.M. Lowman. Biodegradable nanoparticles for drug delivery and targeting. Current Opinion in Solid State and Materials Science, 2002, 6:319~321.
[44] 刘建伟，赵强，万昌秀，医用聚乳酸体内降解机理及应用研究进展，航天医学与医学工程，2001，14：308~310
[45] 中华人民共和国药典 二部（2000年版）中国标准出版社，2000，1250~1251
[46] T. L. Loo, R. L. Dion, et al. The antitumor agent, 1,3-Bis(2-chloroethyl)-1-nitrosourea. J.PHarm.Sci, 1966, 55:492~497
[47]Jain Rajeer A. The manufacturing techniques of various drug loaded biodegradable poly(lactide-co-glycolide) (PLGA) devices, Biomaterials, 2000, 21: 2475~3482
[48] Ti Li Loo, Robert L. Dion. Colorimetric Method for the Determination of 1,3-Bis(2-chloroethyl)-1-nitrosourea. J.PHarm.Sci, 1965, 54:809~810
[49] Oguri S, Sakakibaia T. Clinical pharmacokinetics of carboplatin. J Clin pharmacol, 1988.28~32
[50] 何友兼，姜奇文，管忠震. 卡铂的I期临床试验报告. 1990，9(6)：449~451
[51] Zeller WJ, Bauer S, Remmele T. Interstitial chemotherapy of experimental gliomas, Cancer Treatment Rev. 1990, 17:183~189
[52] Dang W, Colvin OM, Brem H. Covalent coupling of methotrexate to dextran enhances the penetration of cytotoxicity into a tissue-like matrix. Cancer Res. 1994, 54:1729~1735
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