Chinese Academy of Sciences (CAS) Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology of China, No. 11, First North Road, Zhongguancun, Beijing 100190, PR China; University of Chinese Academy of Sciences, Beijing 100049, PR China.
CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, PR China.
Int J Pharm. 2018 Aug 25;547(1-2):582-592. doi: 10.1016/j.ijpharm.2018.05.074. Epub 2018 Jun 1.
Mitochondria are considered the power house of cells where ATP is generated for cellular metabolism, and they also act as a crucial regulator of the intrinsic apoptosis pathway. During ATP synthesis, reactive oxygen species (ROS) are produced as secondary products. Overproduction of ROS can promote mitochondrial DNA mutation, dysfunction and depolarization of the mitochondrial membrane, ultimately resulting in cell death. Therefore, the destruction of mitochondria would be an effective therapeutic approach to kill malignant tumors. Herein, we formulated a PEGylated α-TOS polymeric micellar system loaded with 10-hydroxycamptothecin (HCPT) drug to inhibit the nuclear topoisomerase I enzyme and disrupt the mitochondrial membrane to induce apoptosis. In addition, tumor-penetrating CRGDK peptide-functionalized TPGS specifically bound to the Nrp-1 receptor to facilitate higher cell uptake of polymeric micelles by tumor cells. Experimental studies confirmed that HCPT-loaded and peptide-functionalized TPGS-TOS micelles (HLPFTTM) showed an enhanced anti-cancer effect in A549 cancer cells.
线粒体被认为是细胞的“动力工厂”，在这里生成用于细胞代谢的三磷酸腺苷（ATP），同时也作为细胞内凋亡途径的关键调节因子。在 ATP 合成过程中，会产生作为副产物的活性氧（ROS）。ROS 的过度产生会促进线粒体 DNA 突变、功能障碍和线粒体膜去极化，最终导致细胞死亡。因此，破坏线粒体将是一种有效杀死恶性肿瘤的治疗方法。在这里，我们构建了一种聚乙二醇化的 α-TOS 聚合物胶束系统，负载 10-羟基喜树碱（HCPT）药物，以抑制核拓扑异构酶 I 酶并破坏线粒体膜，从而诱导细胞凋亡。此外，肿瘤穿透性 CRGDK 肽功能化的 TPGS 特异性结合到 Nrp-1 受体上，以促进聚合物胶束被肿瘤细胞更高地摄取。实验研究证实，负载 HCPT 和肽功能化的 TPGS-TOS 胶束（HLPFTTM）在 A549 癌细胞中表现出增强的抗癌效果。
