Department of Pharmaceutics, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China.
Nanoscale. 2021 Jul 15;13(27):11953-11962. doi: 10.1039/d1nr01083b.
Chlorin e6 (Ce6) is a widely utilized photosensitizer in photodynamic therapy (PDT) against tumor growth, but its hydrophobic feature and the hypoxia in the tumor microenvironment greatly compromise its therapeutic efficacy. To address the issues, here we designed a new Ce6 derivative (TCe6) by coupling Ce6 with amphiphilic d-α-tocopherol polyethylene glycol 1000 succinate (TPGS), endowing Ce6 with an excellent amphiphilic feature. In particular, the overall reactive oxygen species (ROS) generation by TCe6 was significantly enhanced because TPGS could interact with mitochondrial complex II to induce extra ROS production, amplifying the total ROS production under PDT. Inspired by the unique property of α-cyano-4-hydroxycinnamate (CHC) in regulating lactate metabolism to spare more intracellular oxygen for PDT, TCe6 was further co-assembled with CHC to construct TCe6/CHC nanoparticles (NPs) for addressing the insufficient oxygen issue in PDT. The as-prepared TCe6/CHC NPs not only increased the efficiency of cell internalization but also improved the solubility and stability of Ce6 and CHC. Thanks to the extra ROS production by the TPGS unit, the amphiphilic feature of TCe6 and the CHC-mediated hypoxia microenvironment, the TCe6/CHC NPs demonstrated excellent PDT against tumor growth. This work provided a versatile strategy to solve the current bottleneck in photosensitizer-based PDT, holding great promise for the design of advanced photodynamic nanoplatforms.
叶绿素 e6（Ce6）是一种广泛应用于光动力疗法（PDT）以抑制肿瘤生长的光敏剂，但它的疏水性以及肿瘤微环境中的缺氧极大地影响了其治疗效果。为了解决这些问题，我们设计了一种新型的 Ce6 衍生物（TCe6），通过将 Ce6 与两亲性的 d-α-生育酚聚乙二醇 1000 琥珀酸酯（TPGS）偶联，赋予 Ce6 优异的两亲性。特别是，由于 TPGS 可以与线粒体复合物 II 相互作用诱导额外的 ROS 产生，从而显著增强了 TCe6 的整体活性氧（ROS）生成，放大了 PDT 下的总 ROS 生成。受 α-氰基-4-羟基肉桂酸（CHC）调节乳酸代谢以在 PDT 中为细胞内提供更多氧气的独特性质的启发，我们进一步将 TCe6 与 CHC 共组装构建 TCe6/CHC 纳米粒子（NPs）以解决 PDT 中氧气不足的问题。所制备的 TCe6/CHC NPs 不仅提高了细胞内化效率，还提高了 Ce6 和 CHC 的溶解度和稳定性。由于 TPGS 单元产生的额外 ROS、TCe6 的两亲性以及 CHC 介导的缺氧微环境，TCe6/CHC NPs 对肿瘤生长具有优异的 PDT 效果。这项工作提供了一种通用策略来解决基于光敏剂的 PDT 当前的瓶颈问题，为先进的光动力纳米平台的设计提供了广阔的前景。
