【摘要】 目的:利用低分子肝素(low molecular weight heparin,LMWH)的亲水性和阿霉素(doxorubicin,DOX)疏水性的特点,合成并制备同时递送2种作用机制不同的药物的LMWH-DOX聚合物胶束,用于抗肿瘤治疗。方法:以乙二胺为连接臂,通过酰胺化和希夫氏碱2步反应合成LMWH-DOX,采用透析法使其在水溶液中自组装形成"核-壳"结构的聚合物胶束。通过1H NMR对合成的LMWH-DOX聚合物进行结构确证。透射电镜观察胶束形态,粒度仪测定聚合物胶束的粒径及Zeta电位,UV测定其载药量。采用芘荧光探针法测定LMWH-DOX胶束的临界胶束浓度(critical micelle concentration,CMC);动态透析法考察LMWH-DOX胶束的体外释药特征;噻唑蓝法考察LMWH-DOX聚合物胶束对4T1细胞及EA. hy926细胞存活率的影响。结果:LMWH-DOX胶束呈类球形;粒径为144. 4 nm; PDI为0. 121; Zeta电位为-36. 5 m V;临界胶束浓度为6. 92×10-6μg·m L-1,载药量为(12. 09±0. 69)%;其体外释药行为表现出酸敏感性特征,对2种细胞株也表现出良好的增殖抑制作用。结论:LMWH-DOX聚合物胶束具有良好的理化性质,作为抗肿瘤药物递送系统具有良好的研究前景。更多还原

【Abstract】 Objective: To prepare low molecular weight heparin-doxorubicin( LMWH-DOX) polymer micelles by conjugating the two kinds of drugs with different water-solubilities and biological effects together.Methods: The DOX grafted LMWH was first synthesized via imine linkage and characterized by1 H NMR. Then the amphiphilic polymer LMWH-DOX was self-assembled into micelles with core-shell structure in aqueous solution.The morphology of LMWH-DOX micelles was observed by transmission electron microscopy( TEM). The particle size and Zeta potential were measured using a Malvern particle size analyzer. The critical micelle concentration( CMC) of LMWH-DOX micelles was detected by fluorescent probe method. The loading capacity and in vitro release of DOX from LMWH-DOX were also investigated. Furthermore,MTT assay was used to study the viability of 4 T1 and EA. hy 926 cells after LMWH-DOX micelles treatment. Results: The LMWH-DOX micelles were spherical with the size of 144. 4 nm and PDI of 0. 121. The Zeta potential was-36. 5 m V,and CMC was 6. 92 × 10-6μg·m L-1. The average drug loading capacity was( 12. 09 ± 0. 69) %. The in vitro drug release behavior of LMWHDOX micelles showed an acid-sensitive characteristic. More importantly,LMWH-DOX micelles displayed good inhibitory effects on cell proliferation of both 4 T1 and EA. hy 926 cells. Conclusion: The prepared LMWH-DOX micelles have good physicochemical properties and are a promising drug delivery system for antitumor treatment.更多还原