College of Pharmaceutical Sciences, Zhejiang University , 866 Yuhangtang Road, Hangzhou, Zhejiang 310058, P. R. China.
ACS Appl Mater Interfaces. 2017 Jun 21;9(24):20385-20398. doi: 10.1021/acsami.7b02606. Epub 2017 Jun 6.
Recently, interest in tumor-targeted and site-specific drug release from nanoparticles as a means of drug delivery has increased. In this study, we report a smart nanosized micelle formed by hyaluronic acid (HA) conjugated with d-α-tocopherol succinate (TOS) using a disulfide bond as the linker (HA-SS-TOS, HSST). HSST micelles can specifically bind to the CD44 receptors that are overexpressed by cancer cells. The high levels of glutathione (GSH) in tumor cells selectively break the disulfide bond linker. This effect results in the synchronous release of the payload and a TOS fragment. These two components subsequently demonstrate synergetic anticancer activity. First, we demonstrate that drug release from HSST occurs rapidly in physiological high redox conditions and inside cancer cells. Significant GSH-triggered drug release was also observed in vivo. Furthermore, an in vivo biodistribution study indicated that the HSST micelles efficiently accumulated at the tumor sites, primarily due to an enhanced permeability and retention effect and the efficient binding to the cancer cells that overexpressed the CD44 receptor. Interestingly, the synchronous release of paclitaxel (PTX) and the TOS fragment from the PTX-loaded HSST caused synergetic tumor cell killing and tumor growth inhibition. Our work presents a useful candidate for a drug delivery system that can specifically accumulate at tumor tissue, selectively release its payload and a TOS fragment, and thus display a synergetic anticancer effect.
近年来，人们对通过纳米粒子实现肿瘤靶向和特定部位药物释放以进行药物输送的兴趣日益增加。在本研究中，我们报告了一种由透明质酸（HA）与 d-α-生育酚琥珀酸酯（TOS）通过二硫键连接形成的智能纳米胶束（HA-SS-TOS，HSST）。HSST 胶束可以特异性结合癌细胞过度表达的 CD44 受体。肿瘤细胞中高水平的谷胱甘肽（GSH）选择性地破坏二硫键连接物。这种效应导致有效载荷和 TOS 片段的同步释放。这两个组件随后表现出协同的抗癌活性。首先，我们证明 HSST 中的药物释放会在生理高氧化还原条件下和癌细胞内迅速发生。体内也观察到了明显的 GSH 触发的药物释放。此外，体内生物分布研究表明，HSST 胶束能够有效地在肿瘤部位积累，主要是由于增强的通透性和保留效应以及与过度表达 CD44 受体的癌细胞的有效结合。有趣的是，从负载紫杉醇（PTX）的 HSST 中同步释放 PTX 和 TOS 片段会协同杀伤肿瘤细胞并抑制肿瘤生长。我们的工作提出了一种有前途的药物输送系统候选物，它可以特异性地在肿瘤组织中积累，选择性地释放其有效载荷和 TOS 片段，从而显示出协同的抗癌作用。
