Enhanced stability of polymeric micelles based on postfunctionalized poly(ethylene glycol)-b-poly(γ-propargyl L-glutamate): the substituent effect.
Enhanced stability of polymeric micelles based on postfunctionalized poly(ethylene glycol)-b-poly(γ-propargyl L-glutamate): the substituent effect.
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DOI：
10.1021/bm201873u
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发表时间：
2012-05-14
影响因子：
6.2
通讯作者：
Hammond PT
中科院分区：
文献类型：
--
作者：
Zhao X;Poon Z;Engler AC;Bonner DK;Hammond PT
延迟聚合物胶束药物递送系统的临床转化的主要障碍之一是这些自组装胶束在静脉内（IV）注射后是否可以在血液中保持其完整性。本研究的目的是评估核心功能化对聚合物胶束的热力学和动力学稳定性的影响。N-羧酸酐（NCA）的开环聚合与高效“点击”偶联的组合使得能够容易且快速地获得具有完全相同嵌段长度的聚（乙二醇）-嵌段-聚（γ-R-谷氨酸盐）家族，其中取代基“R”被调整。用~ 1H NMR、FT-IR和GPC对共聚物的结构进行了表征。使用芘作为荧光探针，发现这些聚合物的临界胶束浓度（CMC）在10−7-10−6 M的范围内，这表明自组装胶束具有良好的热力学稳定性。极性侧基的胶束核心的掺入导致高CMC值，然而，从这些共聚物制备的胶束在血清的存在下，并在SDS干扰动力学更稳定。研究还发现，这些聚合物可以有效地包封紫杉醇（PTX）作为模型抗癌药物，具有更好动力学稳定性的胶束对PTX的初始突释有更好的抑制作用，并表现出更好的PTX缓释效果。这些载有PTX的胶束对HeLa细胞表现出与临床批准的Cremophor® PTX制剂相当的细胞毒性，而嵌段共聚物显示出比Cremophor-乙醇混合物低得多的毒性。目前的工作表明，PEG-b-PPLG可以是一个统一的嵌段共聚物平台，朝着发展的聚合物胶束传递系统，为不同的药物，通过方便的改性的PPLG嵌段。
One of the major obstacles that delay the clinical translation of polymeric micelle drug delivery systems is whether these self-assembled micelles can retain their integrity in blood following intravenous (IV) injection. The objective of this study was to evaluate the impact of core functionalization on the thermodynamic and kinetic stability of polymeric micelles. The combination of ring-opening polymerization of N-carboxyanhydride (NCA) with highly efficient “click” coupling has enabled easy and quick access to a family of poly(ethylene glycol)-block-poly(γ-R-glutamate)s with exactly the same block lengths, for which the substituent “R” is tuned. The structures of these copolymers were carefully characterized by 1H NMR, FT-IR and GPC. Using pyrene as the fluorescence probe, the critical micelle concentrations (CMCs) of these polymers were found to be in the range of 10−7-10−6 M, which indicates good thermodynamic stability for the self-assembled micelles. The incorporation of polar side groups in the micelle core leads to high CMC values; however, micelles prepared from these copolymers are kinetically more stable in the presence of serum and upon SDS disturbance. It was also observed that these polymers could effectively encapsulate paclitaxel (PTX) as a model anticancer drug and the micelles possessing better kinetic stability showed better suppression of the initial “burst” release and exhibited more sustained release of PTX. These PTX-loaded micelles exerted comparable cytotoxicity against HeLa cells as the clinically approved Cremophor® PTX formulation while the block copolymers showed much lower toxicity compared to the Cremophor-ethanol mixture. The present work demonstrated that the PEG-b-PPLG can be a uniform block copolymer platform toward development of polymeric micelle delivery systems for different drugs through the facile modification of the PPLG block.
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