The combination of chemotherapy with photodynamic therapy (PDT) holds promising applications in cancer therapy. However, co-encapsulation of chemotherapeutic agents and photosensitizers (PS) into the conventional nanocarriers suffers from inefficient co-loading and aggregation-caused quenching (ACQ) effect of PS trapped in dense carrier materials. Herein, we report a light-activatable photodynamic PEG-coated prodrug nanoplatform for core-shell synergistic chemo-photodynamic therapy. A novel photodynamic polymer is rationally designed and synthesized by conjugating pyropheophorbide a (PPa) to polyethylene glycol 2000 (PEG2k). PPa is used as the hydrophobic and photodynamic moiety of the amphipathic PPa-PEG2k polymer. Then, a core-shell nanoassembly is prepared, with an inner core of a reactive oxygen species (ROS)-responsive oleate prodrug of paclitaxel (PTX) and an outer layer of PPa-PEG2k. PPa-PEG2k serves for both PEGylation and PDT. Instead of being trapped in the inner core, PPa in the outer PPa-PEG2k layer significantly alleviates the ACQ effect. Under laser irradiation, ROS generated by PPa-PEG2k not only is used for PDT but also synergistically promotes PTX release in combination with the endogenous ROS overproduced in tumor cells. The photodynamic PEG-coated nanoassemblies demonstrated synergistic antitumor activity in vivo. Such a unique nanoplatform, with an inner chemotherapeutic core and an outer photodynamic PEG shell, provides a new strategy for synergistic chemo-photodynamic therapy. STATEMENT OF SIGNIFICATION: The combination of chemotherapy with photodynamic therapy (PDT) holds promising prospects in cancer therapy. However, it remains a tremendous challenge to effectively co-deliver chemotherapeutic drugs and photosensitizers into tumors. Herein, we construct a photodynamic PEGylation-coated prodrug-nanoplatform for high-efficiency synergistic cancer therapy, which is composed of a light-activatable PPa-PEG2k shell and a ROS-responsive paclitaxel (PTX) prodrug core. The PPa-PEG2k-generated ROS not only was used for synergistic PTX release but also synergistically facilitated tumor cell apoptosis in combination with PTX-initiated chemo-cytotoxicity. The light-activatable nanoassemblies exhibited multiple drug delivery advantages including high co-loading efficiency, self-enhanced PTX release, extended circulation time, favorable biodistribution, and potent synergistic anticancer activity. Our findings provide a new strategy for the rational design of advanced nano-DDS for high-efficiency combinational chemo-photodynamic therapy.

中文翻译：

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光动力PEG涂层的ROS敏感前药纳米组件，用于核-壳协同化学光动力疗法。

化学疗法与光动力疗法（PDT）的结合在癌症治疗中具有广阔的应用前景。但是，将化学治疗剂和光敏剂（PS）共封装到常规纳米载体中的做法是，捕获在致密载体材料中的PS的共载效率低，并且聚集引起的猝灭（ACQ）效果不佳。在本文中，我们报告了一种可光激活的光动力PEG涂层前药纳米平台，用于核-壳协同化学光动力疗法。通过将焦脱镁叶绿酸a（PPa）与聚乙二醇2000（PEG2k）共轭，合理地设计和合成了一种新型的光动力学聚合物。PPa用作两亲性PPa-PEG2k聚合物的疏水和光动力部分。然后，制备核-壳纳米组装体，具有紫杉醇（PTX）的活性氧（ROS）响应的油酸酯前药的内芯和PPa-PEG2k的外层。PPa-PEG2k可同时用于PEG化和PDT。PPA-PEG2k外部层中的PPa并未陷在内核中，而是显着减轻了ACQ效应。在激光照射下，由PPa-PEG2k产生的ROS不仅用于PDT，而且与肿瘤细胞中过量产生的内源性ROS结合，协同促进PTX的释放。光动力PEG涂层的纳米组件在体内表现出协同抗肿瘤活性。这种具有内部化学治疗核心和外部光动力PEG外壳的独特纳米平台，为协同化学光动力疗法提供了新的策略。声明：化学疗法与光动力疗法（PDT）的结合在癌症治疗中具有广阔的前景。然而，有效地将化学治疗药物和光敏剂共递送到肿瘤中仍然是巨大的挑战。在本文中，我们构建了一种用于高效率协同癌症治疗的光动力PEG化涂层前药-纳米平台，它由可光激活的PPa-PEG2k外壳和ROS响应紫杉醇（PTX）前药核心组成。PPa-PEG2k生成的ROS不仅用于PTX的协同释放，而且与PTX引发的化学细胞毒性联合协同促进肿瘤细胞凋亡。可光激活的纳米组件具有多种药物输送优势，包括高共载效率，PTX自增强释放，延长循环时间，良好的生物分布，和有效的协同抗癌活性。我们的研究结果为合理设计用于高效联合化学光动力疗法的先进纳米DDS提供了新的策略。