目的 通过酰胺键共价结合方式, 制备泊洛沙姆-多柔比星聚合物(DOX-P), 对该聚合物组装形成的纳米级胶束进行体外表征研究。方法 首先用丁二酸酐激活泊洛沙姆188, 得到末端含羧基的聚合物, 再通过化学反应使多柔比星(DOX)的伯胺基团与所得聚合物末端羧基共轭连接形成偶联物。利用偶联物的在水中的自组装性能, 制备偶联物胶束, 并对其粒径、ξ电位、载药量和临界胶束浓度(CMC)进行测定。结果 泊洛沙姆-多柔比星聚合物胶束在载药量、稳定性方面都优于物理包载多柔比星的泊洛沙姆胶束。通过药物体外释放实验比较, 泊洛沙姆-多柔比星聚合物胶束可以维持释放多柔比星在10 d以上, 而物理包载多柔比星的胶束释放多柔比星只维持2 d。结论 由于临界胶束浓度值低、保持均一纳米级粒径、载药量高和控制药物释放行为, 泊洛沙姆-多柔比星聚合物胶束可能会作为一个新的肿瘤药物递送系统。
Abstract
OBJECTIVE Poloxamer-doxorubicin polymer (DOX-P) was prepared through covalent binding mode via an amide bond, DOX-P can be self-assemble to form nanoscale Characterization and anti-tumor activity of chemical conjugation of doxorubicin (DOX) in polymeric micelles were investigated.METHODS Succinic anhydride activated Poloxamer188 was first synthesized and the primary amine group in doxorubicin was conjugated to the terminal carboxyl of Poloxamer188 via a amide. The resulting polymeric micelles in aqueous solution were characterized by measurement of size, ξ-potential, drug loading and critical micelle concentration. RESULTS DOX-P micelles had superiorities over physically-loaded DOX micelles in loading efficiency, diameter and CMC value. From drug release experiment in vitro, DOX-P micelles reached a sustained release profile for DOX with 10 d while physically-loaded DOX only 2 d. CONCLUSION With low CMC value, high loading efficiency, nanometer diameter and controlled release behaviour, DOX-P micelles might be developed as a new cancer targeted delivery system.
关键词
多柔比星 /
泊洛沙姆188 /
聚合物胶束 /
药物递送系统
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Key words
doxorubicin /
poloxamer188 /
polymeric micelle /
drug delivery system
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中图分类号：
R944
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参考文献
[1] KHANDARE J, MINKO T. Polymer-drug conjugates:Progress in polymeric prodrugs. Prog Polym S, 2006, 31(4):359-397.[2] SCHMOLKA I R. Poloxamers in the Pharmaceutical Industry. Boca Ratin:CRC Press, 1991.[3] CROY S R, KWON G S. Polymeric micelles for drug delivery. Curr Pharm Des, 2006, 12(36):4669-4684.[4] GAUCHER G, DUFRESNE M H, SANT V P, et al. Block copolymer micelles:Preparation, characterization and application in drug delivery. J Controlled Release, 2005, 109(1-3):169-188.[5] BATRAKOVA E V, LI S, BRYNSKIKH A M, et al, Effects of pluronic and doxorubicin on drug uptake, cellular metabolism, apoptosis and tumor inhibition in animal models of MDR cancers. J Controlled Release, 2010, 143(3):290-301.[6] KABANOV A V, BATRAKOVA E V, MILLER D W. Pluronic block copolymers as modulators of drug efflux transporter activity in the blood-brain barrier. Adv Drug Deliv Rev, 2003, 55(1):151-164.[7] BATRAKOVA E V, KABANOV A V. Pluronic block copolymers:Evolution of drug delivery concept from inert nanocarriers to biological response modifiers. J Controlled Release, 2008, 130(2):98-106.[8] SZAKACS G, PATERSON J K. Targeting multidrug resistance in cancer. Nat Rev Drug Discov, 2006, 5(3):219-234.[9] TIAN J L, ZHAO Y Z, JIN Z, et al. Synthesis and characterization of Poloxamer 188-grafted heparin copolymer. Drug Dev Ind Pharm, 2010, 36(7):832-838. LA S B, OKANO T, KATAOKA K. Preparation and characterization of the micelle-forming polymeric drug indomethacin-incorporated poly(ethylene oxide)-poly(beta-benzyl L-aspartate) block copolymer micelles. J Pharm Sci, 1996, 85(1):85-90. YOO H S, PARK T G. Biodegradable polymeric micelles composed of doxorubicin conjugated PLGA-PEG block copolymer. J Controlled Release, 2001, 70(1-2):63-70.
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脚注
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基金
国家自然科学基金资助项目(30901870);全军医学科技青年培育项目(13QNP079)
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