Wang Yin, Wu Fanyu, Yang Tan, Li Bin, Wang Han, Ye Peng, Li Weijie
Department of Laboratory Medicine, Wuhan Hospital of Traditional Chinese and Western Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
Department of Geriatrics, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, China.
Pharmaceutics. 2025 Jul 21;17(7):945. doi: 10.3390/pharmaceutics17070945.
Cisplatin remains a cornerstone chemotherapeutic agent for non-small-cell lung cancer (NSCLC) treatment, yet its clinical utility is substantially limited by acquired resistance and the inadequate suppression of tumor metastasis. Emerging evidence implicates interleukin 6 (IL-6) as a critical mediator of chemoresistance through cancer stem cell (CSC) enrichment and metastasis promotion via epithelial-mesenchymal transition (EMT) induction, ultimately contributing to cisplatin therapy failure. This study sought to address these challenges by designing a nanoplatform with two innovative aims: (1) to achieve active tumor targeting through binding to the IL-6 receptor (IL-6R), and (2) to concurrently inhibit IL-6-mediated chemoresistance signaling pathways. A lipid-polymer hybrid nanoparticle (LPC) encapsulating cisplatin was synthesized and subsequently surface-functionalized with tocilizumab (TCZ), a monoclonal antibody that targets IL-6R. The therapeutic efficacy of this TCZ-modified nanoparticle (LPC-TCZ) was assessed through a series of in vitro and in vivo experiments, focusing on the inhibition of EMT, expression of CSC markers, tumor growth, and metastasis. Systematic in vitro and in vivo evaluations revealed that LPC-TCZ synergistically attenuated both EMT progression and CSC marker expression through the targeted blockade of IL-6/STAT3 signaling. This multimodal therapeutic strategy demonstrated superior tumor growth inhibition and metastatic suppression compared to conventional cisplatin monotherapy. Our findings establish a nanotechnology-enabled approach to potentiate cisplatin efficacy by simultaneously countering chemoresistance mechanisms and metastatic pathways in NSCLC management.
顺铂仍然是治疗非小细胞肺癌（NSCLC）的一种基石性化疗药物，但其临床应用因获得性耐药和对肿瘤转移抑制不足而受到极大限制。新出现的证据表明，白细胞介素6（IL-6）是化疗耐药的关键介质，它通过富集癌症干细胞（CSC）和诱导上皮-间质转化（EMT）促进转移，最终导致顺铂治疗失败。本研究旨在通过设计一种具有两个创新目标的纳米平台来应对这些挑战：（1）通过与IL-6受体（IL-6R）结合实现主动肿瘤靶向，（2）同时抑制IL-6介导的化疗耐药信号通路。合成了一种包裹顺铂的脂质-聚合物杂化纳米颗粒（LPC），随后用靶向IL-6R的单克隆抗体托珠单抗（TCZ）进行表面功能化修饰。通过一系列体外和体内实验评估了这种经TCZ修饰的纳米颗粒（LPC-TCZ）的治疗效果，重点关注对EMT的抑制、CSC标志物的表达、肿瘤生长和转移。系统的体外和体内评估表明，LPC-TCZ通过靶向阻断IL-6/STAT3信号通路，协同减弱了EMT进程和CSC标志物的表达。与传统的顺铂单药治疗相比，这种多模式治疗策略在抑制肿瘤生长和转移方面表现出更优的效果。我们的研究结果建立了一种基于纳米技术的方法，通过同时对抗NSCLC治疗中的化疗耐药机制和转移途径来增强顺铂的疗效。
