Department of Pharmaceutics, College of Pharmacy, Shandong University, Jinan 250012, China.
Department of Pharmaceutics, College of Pharmacy, Shandong University, Jinan 250012, China.
J Colloid Interface Sci. 2017 Apr 15;492:101-111. doi: 10.1016/j.jcis.2016.12.046. Epub 2016 Dec 23.
Doxorubicin (DOX) is one of the most common chemotherapeutic agents for the treatment of various cancers, but its clinical usage is limited by dose-dependent cardiotoxicity. We have recently synthesized a series of Chondroitin sulfate/poly (d,l-lactideco-glycolide) block copolymers (Chs-b-PLGA) with different length of hydrophobic block by an end-to-end coupling strategy. The structure of the amphiphilic block copolymers with low critical micelle concentration (∼28mg/L) were confirmed by H NMR. The copolymers could self-assemble into stable micelles in aqueous environment with homogeneous size distribution and negative zeta potential. The hemolytic study indicated their excellent blood compatibility and potential application for intravenous administration. DOX can be efficiently encapsulated by the Chs-b-PLGA micelles. The DOX-loaded micelles showed a sustained and pH dependent drug release behavior. The cytotoxicity assay showed no associated toxicity with blank micelles while concentration-related cell inhibition with DOX-loaded micelles. Moreover, fast cellular uptake of DOX-loaded micelles was observed by fluorescent microscope. In vivo pharmacokinetics study showed that the Chs-b-PLGA micelles could significantly prolong the blood circulation time of DOX. The maximum tolerated dose (MTD) of DOX-loaded micelles in Kunming mice was about 2-fold higher of the MTD of free DOX, indicating a high tolerance of the DOX-loaded micelles. In conclusion, the Chs-b-PLGA micelles would be a potentially useful drug delivery system for cancer therapy.
多柔比星（DOX）是治疗各种癌症最常用的化疗药物之一，但由于其剂量依赖性心脏毒性，其临床应用受到限制。我们最近通过端到端偶联策略合成了一系列不同疏水性嵌段长度的硫酸软骨素/聚（DL-丙交酯-co-乙交酯）嵌段共聚物（Chs-b-PLGA）。具有低临界胶束浓度（约 28mg/L）的两亲嵌段共聚物的结构通过 1 H NMR 得到证实。共聚物在水相环境中可以自组装成稳定的胶束，具有均匀的粒径分布和负的 Zeta 电位。溶血研究表明它们具有优异的血液相容性，有潜力用于静脉注射。DOX 可以被 Chs-b-PLGA 胶束高效包载。载 DOX 的胶束表现出持续的、依赖 pH 的药物释放行为。细胞毒性试验表明空白胶束无相关毒性，而载 DOX 胶束具有浓度相关的细胞抑制作用。此外，荧光显微镜观察到载 DOX 胶束的细胞摄取速度较快。体内药代动力学研究表明，Chs-b-PLGA 胶束可以显著延长 DOX 的血液循环时间。载 DOX 胶束在昆明小鼠中的最大耐受剂量（MTD）约为游离 DOX 的 MTD 的 2 倍，表明载 DOX 胶束具有较高的耐受性。总之，Chs-b-PLGA 胶束可能是一种有前途的癌症治疗药物递送系统。
