Yang Manseok, Kim Sujin, Jeong Seungwon, Lee Suyeon, Lee Seunga, Jo Hanui, Kim Nuri, Song Nanhee, Park Seong-Cheol, Lee Dongwon
Department of Bionanotechnology and Bioconvergence Engineering, Jeonbuk National University, Jeonju, Jeonbuk 54896, Korea.
Department of Polymer Engineering, Suncheon National University, Suncheon, Chonnam 57922, Korea.
Biomacromolecules. 2025 Jan 13;26(1):437-448. doi: 10.1021/acs.biomac.4c01250. Epub 2024 Dec 9.
Targeting the altered redox balance in cancer cells, this study explores a strategy to induce selective cancer cell death by combining reactive oxygen species (ROS) generation with glutathione (GSH) depletion. We developed oxidative stress-amplifying polymeric (pCB) micelles that function both as therapeutic agents and carriers for GSH-depleting retinoic acid prodrug (BRDP). pCB incorporating ROS-generating cinnamaldehyde and a GSH-depleting quinone methide precursor could self-assemble into micelles encapsulating BRDP, delivering both ROS generators and GSH-depleting drugs. The micelles were surface-functionalized with the tripeptide Arg-Gly-Asp (RGD) for targeted delivery to integrin-overexpressing tumors. In a mouse xenograft model, RGD-decorated BRDP-loaded micelles significantly accumulated in tumor sites, enhancing anticancer efficacy without toxicity to normal tissues. This study marks significant advancement in the field of oxidative stress-amplifying polymeric precursors, presenting a novel and highly effective anticancer therapeutic approach that integrates multiple tumor-specific triggers and ROS-mediated mechanisms.
针对癌细胞中改变的氧化还原平衡，本研究探索了一种通过将活性氧（ROS）生成与谷胱甘肽（GSH）耗竭相结合来诱导选择性癌细胞死亡的策略。我们开发了氧化应激放大聚合物（pCB）胶束，其既作为治疗剂，又作为用于耗竭GSH的视黄酸前药（BRDP）的载体。掺入产生ROS的肉桂醛和耗竭GSH的醌甲基化物前体的pCB可以自组装成包裹BRDP的胶束，递送ROS生成剂和耗竭GSH的药物。胶束用三肽精氨酸-甘氨酸-天冬氨酸（RGD）进行表面功能化，以靶向递送至整合素过表达的肿瘤。在小鼠异种移植模型中，RGD修饰的负载BRDP的胶束在肿瘤部位显著积累，增强了抗癌疗效且对正常组织无毒性。本研究标志着氧化应激放大聚合物前体领域的重大进展，提出了一种整合多种肿瘤特异性触发因素和ROS介导机制的新型高效抗癌治疗方法。
