School of Biomedical Engineering & Guangdong Provincial Key Laboratory of Construction and Detection in Tissue Engineering, Southern Medical University, Guangzhou 510515, P. R. China.
School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou 511436, P. R. China.
Biomater Sci. 2022 Dec 20;11(1):162-169. doi: 10.1039/d2bm01320g.
Tumor cells activate DNA repair pathways to combat the oxidative damage induced by reactive oxygen species (ROS), contributing to their resistance to photodynamic therapy (PDT). Herein, a self-delivery photodynamic sensitizer is developed to enhance oxidative damage by blocking the DNA repair pathway through poly(ADP-ribose) polymerase (PARP) inhibition. Specifically, the photodynamic sensitizer (CeOla) is constructed based on the self-assembly of the photosensitizer chlorine e6 (Ce6) and the PARP inhibitor olaparib (Ola). Of note is that carrier free CeOla has a high drug content and favorable water stability, which could be effectively internalized by tumor cells for robust PDT upon light irradiation. Moreover, CeOla could inhibit the activation of PARP, promote the upregulation of γ-H2AX and reduce the expression of Rad51, thereby blocking the DNA repair pathway to sensitize tumor cells for PDT. As a consequence, the self-delivery CeOla greatly promotes the tumor cell apoptosis and shows a high antitumor performance with low side effects. It serves as a novel platform for the development of self-delivery nanomedicine to overcome oxidative resistance in tumor treatment.
肿瘤细胞激活 DNA 修复途径以对抗活性氧（ROS）诱导的氧化损伤，从而使其对光动力疗法（PDT）产生抗性。在此，通过抑制聚（ADP-核糖）聚合酶（PARP），开发了一种自递送的光动力敏化剂来增强氧化损伤。具体而言，基于光敏剂氯 e6（Ce6）和 PARP 抑制剂奥拉帕利（Ola）的自组装构建了光动力敏化剂（CeOla）。值得注意的是，无载体的 CeOla 具有高药物含量和良好的水分稳定性，可在光照下被肿瘤细胞有效内化，从而实现强大的 PDT。此外，CeOla 可以抑制 PARP 的激活，促进 γ-H2AX 的上调并降低 Rad51 的表达，从而阻断 DNA 修复途径，使肿瘤细胞对 PDT 敏感。结果，自递送的 CeOla 大大促进了肿瘤细胞凋亡，并表现出低副作用的高效抗肿瘤性能。它为克服肿瘤治疗中的氧化抗性而开发自递送纳米医学提供了一个新平台。
