Liu Guohao, Wang Bing, Chen Ping, Li Zhiqian, Cheng Xinying, Gong Qiyong, Luo Kui
Department of Radiology, Huaxi MR Research Center (HMRRC), Institution of Radiology and Medical Imaging, Breast Center, Institute of Breast Health Medicine, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China.
Department of Radiology, Huaxi MR Research Center (HMRRC), Institution of Radiology and Medical Imaging, Breast Center, Institute of Breast Health Medicine, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China; Functional and Molecular Imaging Key Laboratory of Sichuan Province, Research Unit of Psychoradiology, Chinese Academy of Medical Sciences, Chengdu 610041, China; Xiamen Key Lab of Psychoradiology and Neuromodulation, Department of Radiology, West China Xiamen Hospital of Sichuan University, Xiamen 361021, China.
Acta Biomater. 2025 Jun 22. doi: 10.1016/j.actbio.2025.06.038.
Application of microtubule-targeting agents (MTAs) for triple-negative breast cancer (TNBC) is hampered by their limited efficacy and strong systemic toxicity. Herein, we reported dendritic copolymer-drug conjugates to synergistically disrupt microtubule dynamics and induce therapeutic mitochondrial autophagy (mitophagy), thus enhancing therapeutic efficacy of MTAs. Paclitaxel (PTX) and 2-methoxyestradiol (2ME) were conjugated to glutathione-stimuli responsive dendritic copolymers, resulting in DDS-PTX and DDS-2ME, respectively. PTX and 2ME were tumor-specifically released from DDS-PTX and DDS-2ME, and simultaneously acted on microtubule polymerization and depolymerization, respectively. Dual perturbation of microtubules triggered catastrophic microtubule network collapse, prolonged mitotic arrest and amplified mitochondrial stress. Mechanistically, severe mitotic stress activated the PINK1/Parkin pathway, driving excessive mitophagy and caspase-dependent apoptosis. In a murine TNBC model, treatment with combined DDS-PTX and DDS-2ME resulted in a tumor inhibition rate of 95.01 %, and the median survival was significantly extended compared to monotherapies with DDS-PTX or DDS-2ME. This combined formulation also remarkably reduced side effects of free PTX and 2ME. Mitophagy-mediated apoptotic amplification was explored as a therapeutic paradigm in this study to bridge cytoskeletal disruption with organelle-level vulnerability for enhanced tumor therapy. STATEMENT OF SIGNIFICANCE: Distinct redox-responsive dendritic copolymer-drug conjugates (DDS-PTX and DDS-2ME) were constructed to deliver paclitaxel and 2-methoxyestradiol for synergistic triple-negative breast cancer therapy. Tumor-specific drug release enabled spatiotemporal coordination of microtubule stabilization and depolymerization, thus inducing catastrophic microtubule fragmentation, prolonged mitotic arrest, and amplified mitochondrial stress. These effects subsequently triggered PINK1/Parkin-mediated therapeutic mitophagy and caspase-dependent apoptosis, achieving a 95.01 % tumor suppression rate and extending median survival to 56 days in murine models. Notably, the conjugates significantly reduced systemic toxicity compared to free drugs while maintaining hemocompatibility and organ safety. By integrating molecular-scale tumor microenvironment responsiveness with cytoskeletal-organelle crosstalk, this work establishes a mechanistically driven paradigm to amplify subcellular stress responses, offering a transformative strategy for refractory cancers with enhanced efficacy and safety.
微管靶向剂（MTAs）在三阴性乳腺癌（TNBC）治疗中的应用受到其有限疗效和强烈全身毒性的阻碍。在此，我们报道了树枝状共聚物 - 药物偶联物，其可协同破坏微管动力学并诱导治疗性线粒体自噬（线粒体自噬），从而增强MTAs的治疗效果。紫杉醇（PTX）和2 - 甲氧基雌二醇（2ME）与谷胱甘肽刺激响应性树枝状共聚物偶联，分别得到DDS - PTX和DDS - 2ME。PTX和2ME从DDS - PTX和DDS - 2ME中肿瘤特异性释放，并分别同时作用于微管聚合和解聚。微管的双重扰动引发灾难性的微管网络崩溃、延长有丝分裂停滞并放大线粒体应激。机制上，严重的有丝分裂应激激活PINK1 / Parkin途径，驱动过度的线粒体自噬和半胱天冬酶依赖性凋亡。在小鼠TNBC模型中，联合使用DDS - PTX和DDS - 2ME治疗导致肿瘤抑制率为95.01％，与使用DDS - PTX或DDS - 2ME的单一疗法相比，中位生存期显著延长。这种联合制剂还显著降低了游离PTX和2ME的副作用。本研究探索了线粒体自噬介导的凋亡放大作为一种治疗模式，以弥合细胞骨架破坏与细胞器水平的脆弱性，从而增强肿瘤治疗效果。重要意义声明：构建了独特的氧化还原响应性树枝状共聚物 - 药物偶联物（DDS - PTX和DDS - 2ME），用于递送紫杉醇和2 - 甲氧基雌二醇以协同治疗三阴性乳腺癌。肿瘤特异性药物释放实现了微管稳定和解聚的时空协调，从而诱导灾难性的微管断裂、延长有丝分裂停滞并放大线粒体应激。这些效应随后触发PINK1 / Parkin介导的治疗性线粒体自噬和半胱天冬酶依赖性凋亡，在小鼠模型中实现了95.01％的肿瘤抑制率，并将中位生存期延长至56天。值得注意的是，与游离药物相比，偶联物显著降低了全身毒性，同时保持血液相容性和器官安全性。通过整合分子尺度的肿瘤微环境响应性与细胞骨架 - 细胞器串扰，本研究建立了一种机制驱动的模式来放大亚细胞应激反应，为难治性癌症提供了一种具有更高疗效和安全性的变革性策略。
