Multifunctional polymeric micelles with folate-mediated cancer cell targeting and pH-triggered drug releasing properties for active intracellular drug delivery
Multifunctional polymeric micelles with folate-mediated cancer cell targeting and pH-triggered drug releasing properties for active intracellular drug delivery
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DOI：
10.1039/b500266d
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发表时间：
2005-09-01
影响因子：
--
通讯作者：
Kataoka, K
中科院分区：
文献类型：
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作者：
Bae, Y;Jang, WD;Kataoka, K
本研究制备并表征了一种用于细胞内主动给药的新型多功能聚合物胶束药物载体。该胶束是一种具有球形核 - 壳结构的纳米超分子组装体，其表面和核分别用针对癌细胞的导向分子以及用于控制药物释放的pH敏感型药物结合连接体进行了修饰。为了制备这种胶束，通过在形成壳的聚乙二醇（PEG）链末端安装一种增强细胞内转运的分子促进剂叶酸（Fol），并通过酸敏感的腙键将抗癌药物阿霉素（ADR）连接到形成核的聚天冬氨酸（PAsp）链段的侧链上，专门设计并合成了自组装两亲性嵌段共聚物叶酸 - 聚乙二醇 - 聚（天冬氨酸腙阿霉素）[Fol - PEG - P(Asp - Hyd - ADR)]。由于叶酸结合蛋白（FBP）在癌细胞膜上选择性过表达，叶酸结合的胶束（FMA）可被引导至体内的癌细胞，并且在胶束进入细胞后，腙键会被细胞内酸性环境（pH 5 - 6）裂解，从而使胶束的药物释放曲线受pH控制。在这方面，通过表面等离子体共振（SPR）测量评估了所制备的FMA与FBP结合的选择性。使用人咽癌细胞（KB细胞）的四唑盐染料法（MTT测定）表明，由于叶酸分子与其受体之间的选择性强相互作用，尽管暴露时间较短，但FMA显著提高了细胞生长抑制活性。随后的流式细胞术分析表明，细胞对FMA的摄取显著增加。因此，这些发现将为使用靶向细胞内环境的超分子药物载体治疗癌症提供最有效的方法之一。
A new type of multifunctional polymeric micelle drug carrier for active intracellular drug delivery was prepared and characterized in this study. The micelle is a nano - supramo lecular assembly with a spherical core-shell structure, and its surface and core were modified with piloting molecules for cancer cells and pH-sensitive drug binding linkers for controlled drug release, respectively. In order to prepare such micelles, self-assembling amphiphilic block copolymers, folate-poly(ethylene glycol)-poly(aspartate hydrazone adriamycin) [Fol-PEG-P(Asp-Hyd-ADR)], were specially designed and synthesized by installing a molecular promoter to enhance intracellular transport, folate (Fol), at the end of the shell-forming PEG chain and conjugating the anticancer drug, adriamycin (ADR), to the side chain of the core-forming PAsp segment through an acid-sensitive hydrazone bond. Because folate-binding proteins (FBP) are selectively overexpressed on the cancer cell membranes, the folate-bound micelles (FMA) can be guided to the cancer cells in the body, and after the micelles enter the cells, hydrazone bonds are cleaved by the intracellular acidic environment (pH 5-6) so that the drug release profile of the micelles is controlled pH-dependently. In this regard, FBP-binding selectivity of the prepared FMA was evaluated by surface plasmon resonance (SPR) measurements. The tetrazolium dye method (MTT assay) using human pharyngeal cancer cells (KB cell) revealed that FMA significantly improved cell growth inhibitory activity in spite of a short exposure time due to the selective and strong interaction between folate molecules and their receptors. Subsequent flow cytometric analysis showed that cellular uptake of FMA significantly increased. Consequently, these findings would provide one of the most effective approaches for cancer treatment using intracellular environment- targeting supramolecular drug carriers.