Key Laboratory of Molecular Target and Clinical Pharmacology and the State Key Laboratory of Respiratory Disease and The Fifth Affiliated Hospital, School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou 511436, China; The Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou 511260, China.
Center of Cancer Research, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou 510260, China.
Eur J Pharm Sci. 2023 Oct 1;189:106561. doi: 10.1016/j.ejps.2023.106561. Epub 2023 Aug 8.
Delivering traditional DNA-damaging anticancer drugs into mitochondria to damage mitochondria is a promising chemotherapy strategy. The impermeability of this mitochondrial inner membrane, however, impedes the delivery of drug molecules that could impact other important biological roles of mitochondria. Herein, the prodrug camptothecin (CPT)-triphenylphosphine (TPP) modified with hyaluronic acid (HA) via electrostatic adsorption (HA/CPT-TPP, HCT) was used to mediate the mitochondrial accumulation of CPT. These nanoparticles (NPs) showed enhanced drug accumulation in cancer cells through tumor targeting. HCT entered acidic lysosomes through endosomal transport, HA was degraded by hyaluronidase (HAase) in acidic lysosomes, and the positively charged CPT-TPP was exposed and accumulated fully in the mitochondria. Subsequently, CPT-TPP significantly disrupted the mitochondrial structure and damaged mitochondrial function, leading to increased reactive oxygen species (ROS) levels and energy depletion. Finally, HCT enhanced lung cancer cell apoptosis via the activation of caspase-3 and caspase-9. Furthermore, greatly increased tumor growth inhibition was observed in nude mice bearing A549 xenograft tumors after the administration of HCT via tail injection. This study demonstrated that the mitochondria-targeted delivery of CPT may be a promising antitumor therapeutic strategy.
将传统的 DNA 损伤抗癌药物递送到线粒体以损伤线粒体是一种很有前途的化疗策略。然而，这种线粒体内膜的不透性阻碍了药物分子的传递，这些药物分子可能会影响线粒体的其他重要生物学功能。在此，通过静电吸附（HA/CPT-TPP，HCT）将喜树碱（CPT）-三苯基膦（TPP）与透明质酸（HA）偶联，用于介导 CPT 的线粒体积累。这些纳米颗粒（NPs）通过肿瘤靶向作用增强了癌细胞中的药物积累。HCT 通过内体转运进入酸性溶酶体，HA 在酸性溶酶体中被透明质酸酶（HAase）降解，带正电荷的 CPT-TPP 暴露并完全积累在线粒体中。随后，CPT-TPP 显著破坏线粒体结构并损害线粒体功能，导致活性氧（ROS）水平增加和能量耗竭。最后，HCT 通过激活 caspase-3 和 caspase-9 增强了肺癌细胞的凋亡。此外，尾静脉注射 HCT 后，荷 A549 移植瘤裸鼠的肿瘤生长抑制率大大提高。本研究表明，CPT 的线粒体靶向递送可能是一种很有前途的抗肿瘤治疗策略。
