Department of Maxillofacial Biomedical Engineering & Institute of Oral Biology, School of Dentistry, Kyung Hee University, Seoul, Republic of Korea.
Biomaterials. 2012 Feb;33(5):1489-99. doi: 10.1016/j.biomaterials.2011.11.013. Epub 2011 Nov 29.
A robust core-shell-corona micelle bearing redox-responsive shell-specific cross-links was evaluated as a carrier of docetaxel (DTX) for cancer therapy. The polymer micelles of poly(ethylene glycol)-b-poly(L-lysine)-b-poly(L-phenylalanine) (PEG-PLys-PPhe) in the aqueous phase provided the three distinct functional domains: the PEG outer corona for prolonged circulation, the PLys middle shell for disulfide cross-linking, and the PPhe inner core for DTX loading. The shell cross-linking was performed by the reaction of disulfide-containing cross-linkers with Lys moieties in the middle shells. The shell cross-linking did not change the micelle size or the spherical morphology. The shell cross-linked micelles exhibited enhanced serum stability. The DTX release from the DTX-loaded disulfide cross-linked micelles (DTX-SSCLM) was facilitated by increasing the concentration of glutathione (GSH). At an intracellular GSH level, DTX release was facilitated due to the reductive cleavage of the disulfide cross-links in the shell domains. The in vivo tissue distribution and tumor accumulation of the DTX-SSCLM that were labeled with a near-infrared fluorescence (NIRF) dye, Cy5.5, were monitored in MDA-MB231 tumor-bearing mice. Non-invasive real-time optical imaging results indicated that the DTX-SSCLM exhibited enhanced tumor specificity due to the prolonged stable circulation in blood and the enhanced permeation and retention (EPR) effect compared with the DTX-loaded non-cross-linked micelles (DTX-NCLM). The DTX-SSCLM exhibited enhanced therapeutic efficacy in tumor-bearing mice compared with free DTX and DTX-NCLM. The domain-specific shell cross-linking that is described in this work may serve as a useful guidance for enhancing the antitumor therapeutic efficacy of various polymer micelles and nano-aggregates.
一种具有氧化还原响应性壳特异性交联的坚固核壳冠状胶束被评估为用于癌症治疗的多西紫杉醇（DTX）的载体。聚乙二醇-b-聚（L-赖氨酸）-b-聚（L-苯丙氨酸）（PEG-PLys-PPhe）的聚合物胶束在水相中提供了三个不同的功能域：用于延长循环的 PEG 外冠，用于二硫键交联的 PLys 中间壳和用于 DTX 加载的 PPhe 内核。壳交联通过含有二硫键的交联剂与中间壳中的 Lys 部分的反应进行。壳交联不会改变胶束的尺寸或球形形态。壳交联胶束表现出增强的血清稳定性。DTX 从负载 DTX 的二硫键交联胶束（DTX-SSCLM）的释放通过增加谷胱甘肽（GSH）的浓度来促进。在细胞内 GSH 水平下，由于壳域中二硫键的还原断裂，促进了 DTX 的释放。用近红外荧光（NIRF）染料 Cy5.5 标记的 DTX-SSCLM 的体内组织分布和肿瘤积累在 MDA-MB231 荷瘤小鼠中进行了监测。非侵入性实时光学成像结果表明，与负载 DTX 的非交联胶束（DTX-NCLM）相比，DTX-SSCLM 由于在血液中延长的稳定循环和增强的渗透和保留（EPR）效应，表现出增强的肿瘤特异性。与游离 DTX 和 DTX-NCLM 相比，DTX-SSCLM 在荷瘤小鼠中表现出增强的治疗效果。本文所述的域特异性壳交联可为增强各种聚合物胶束和纳米聚集体的抗肿瘤治疗效果提供有用的指导。
