Hyaluronic Acid-Based pH-Sensitive Polymer-Modified Liposomes for Cell-Specific Intracellular Drug Delivery Systems
Hyaluronic Acid-Based pH-Sensitive Polymer-Modified Liposomes for Cell-Specific Intracellular Drug Delivery Systems
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DOI：
10.1021/acs.bioconjchem.7b00551
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发表时间：
2018-01-01
影响因子：
4.7
通讯作者：
Kono, Kenji
中科院分区：
文献类型：
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作者：
Miyazaki, Maiko;Yuba, Eiji;Kono, Kenji
为了提高抗癌药物在肿瘤化疗中的疗效和减少副作用，迫切需要开发具有肿瘤特异性和肿瘤细胞内控释功能的给药系统。pH敏感性脂质体可用作细胞内药物递送系统，因为它们能够通过具有弱酸性环境的内体的融合或去稳定化将其内容物转移到细胞内部。我们早先报道了基于合成聚合物和生物聚合物的各种类型的pH敏感聚合物修饰的脂质体作为细胞内药物递送系统的载体。在这项研究中，基于透明质酸（HA）的pH敏感性聚合物被设计为不仅具有pH敏感性，而且还具有针对表达CD 44的细胞的靶向特性的多功能聚合物，CD 44被称为癌细胞表面标志物。通过与各种二羧酸酐反应，合成了两种类型的羧基引入的HA衍生物，MGlu-HA和CHex-HA，其具有比MGlu-HA更疏水的侧链结构。这些聚合物修饰的脂质体在中性pH下稳定，但在弱酸性条件下显示内容物释放。CHex-HA修饰的脂质体比HA修饰的或MGlu-HA修饰的脂质体或未修饰的脂质体更有效地将其内容物递送到表达CD 44的细胞中，而相同的脂质体仅被表达较少的CD 44蛋白的细胞略微摄取。因此，HA衍生物修饰的脂质体可用作细胞特异性细胞内药物递送系统。
For the enhancement of therapeutic effects and reduction of side effects derived from anticancer drugs in cancer chemotherapy, it is imperative to develop drug delivery systems with cancer-specificity and controlled release function inside cancer cells. pH-sensitive liposomes are useful as an intracellular drug delivery system because of their abilities to transfer their contents into the cell interior through fusion or destabilization of endosome, which has weakly acidic environment. We earlier reported liposomes modified with various types of pH-sensitive polymers based on synthetic polymers and biopolymers as vehicles for intracellular drug delivery systems. In this study, hyaluronic acid (HA)-based pH-sensitive polymers were designed as multifunctional polymers having not only pH-sensitivity but also targeting properties to cells expressing CD44, which is known as a cancer cell surface marker. Carboxyl group-introduced HA derivatives of two types, MGlu-HA and CHex-HA, which have a more hydrophobic side chain structure than that of MGlu-HA, were synthesized by reaction with various dicarboxylic anhydrides. These polymer-modified liposomes were stable at neutral pH, but showed content release under weakly acidic conditions. CHex-HA-modified liposomes delivered their contents into CD44-expressing cells more efficiently than HA-modified or MGlu-HA-modified liposomes or unmodified liposomes, whereas the same liposomes were taken up only slightly by cells expressing CD44 proteins less. Competition assay using free HA or other polymers revealed that HA derivative-modified liposomes might be recognized by CD44. Therefore, HA-derivative-modified liposomes are useful as cell-specific intracellular drug delivery systems.