†Polymer Science Group, Department of Chemical and Biomolecular Engineering, University of Melbourne, Parkville, Melbourne, Victoria 3010, Australia.
‡CSIRO Manufacturing Flagship, Clayton South, Victoria 3169, Australia.
Biomacromolecules. 2015 Aug 10;16(8):2463-74. doi: 10.1021/acs.biomac.5b00692. Epub 2015 Jul 20.
Novel cisplatin (CDDP)-loaded, polypeptide-based vesicles for the targeted delivery of cisplatin to cancer cells have been prepared. These vesicles were formed from biocompatible and biodegradable maleimide-poly(ethylene oxide)114-b-poly(L-glutamic acid)12 (Mal-PEG114-b-PLG12) block copolymers upon conjugation with the drug itself. CDDP conjugation forms a short, rigid, cross-linked, drug-loaded, hydrophobic block in the copolymer, and subsequently induces self-assembly into hollow vesicle structures with average hydrodynamic diameters (Dh) of ∼ 270 nm. CDDP conjugation is critical to the formation of the vesicles. The reactive maleimide-PEG moieties that form the corona and inner layer of the vesicles were protected via formation of a reversible Diels-Alder (DA) adduct throughout the block copolymer synthesis so as to maintain their integrity. Drug release studies demonstrated a low and sustained drug release profile in systemic conditions (pH = 7.4, [Cl(-)] = 140 mM) with a higher "burst-like" release rate being observed under late endosomal/lysosomal conditions (pH = 5.2, [Cl(-)] = 35 mM). Further, the peripheral maleimide functionalities on the vesicle corona were conjugated to thiol-functionalized folic acid (FA) (via in situ reduction of a novel bis-FA disulfide, FA-SS-FA) to form an active targeting drug delivery system. These targeting vesicles exhibited significantly higher cellular binding/uptake into and dose-dependent cytotoxicity toward cancer cells (HeLa) compared to noncancerous cells (NIH-3T3), which show high and low folic acid receptor (FR) expression, respectively. This work thus demonstrates a novel approach to polypeptide-based vesicle assembly and a promising strategy for targeted, effective CDDP anticancer drug delivery.
已制备出用于将顺铂靶向递送至癌细胞的新型载顺铂的多肽基囊泡。这些囊泡由生物相容和可生物降解的马来酰亚胺-聚（乙二醇）114-b-聚（L-谷氨酸）12（Mal-PEG114-b-PLG12）嵌段共聚物与药物本身缀合后形成。CDDP 缀合形成短的刚性交联的载药疏水性嵌段共聚物，随后诱导自组装成平均水动力直径（Dh）约为 270nm 的空心囊泡结构。CDDP 缀合对于囊泡的形成至关重要。形成囊泡冠层和内层的反应性马来酰亚胺-PEG 部分通过在整个嵌段共聚物合成过程中形成可逆 Diels-Alder（DA）加合物而得到保护，以保持其完整性。药物释放研究表明，在系统条件（pH = 7.4，[Cl(-)] = 140mM）下具有低且持续的药物释放曲线，在晚期内涵体/溶酶体条件（pH = 5.2，[Cl(-)] = 35mM）下观察到更高的“爆发样”释放率。此外，囊泡冠层上的外围马来酰亚胺官能团通过还原新型双 FA 二硫化物 FA-SS-FA 与巯基化叶酸（FA）缀合，形成主动靶向药物递送系统。与非癌细胞（NIH-3T3）相比，这些靶向囊泡表现出明显更高的细胞结合/摄取以及对癌细胞（HeLa）的剂量依赖性细胞毒性，这表明它们具有高和低叶酸受体（FR）表达。因此，这项工作展示了一种基于多肽的囊泡组装的新方法，以及针对靶向、有效的顺铂抗癌药物递送的有前途的策略。
