新型肺鳞癌靶向智能递药系统共载两种化疗药物协同提高抗癌效果的机制研究

Currently, there is no particularly effective drug for clinical treatment of lung squamous carcinoma. Because 10%-20% of patients of lung squamous cell carcinoma have high expression of FGFR1, according to individualized treatment strategies, based on the cognition of clinical dosage forms’ defects of existing small molecule anticancer drugs and gene expressing differences between different lung cancer classifications, this project is proposed to design and synthesize several functional polymer materials, and establish one type of intelligent tbFGF-mediated and pH responsive nano-sized drug delivery system, which encapsulates paclitaxel and aspirin derivative together and is able to exert specific targeting effect, as well as dual drug synergistic anti-tumor effect, to lung squamous carcinoma tissue with high FGFR expression level. We will study this drug delivery system’s physicochemical characteristics and anti-tumor effects from the perspectives of nano-sized carrier establishment, in vitro cellular evaluation, Zebrafish heart micro cavity transplant carcinoma model evaluation, and in vivo pharmacodynamics, pharmacokinetics and tissue distribution studies on tumor-burdened mice model. We also aim elucidate the molecular mechanisms of active targeting effects on tumor and intelligent stepwise drug release behavior, as well as the dialogue mechanism between the signaling pathways of two anti-tumor chemotherapy agents. The results of this project will provide new approaches and new ideas for improving the treatment efficacy of lung squamous cell carcinoma, and reduced the toxicity to patients. Therefore, this project is worthy of implementation.

目前临床上还没有一种针对肺鳞癌的特效药。由于10%-20%的肺鳞癌患者存在FGFR1高表达, 故根据个体化治疗策略，本项目拟针对小分子抗肿瘤药物现有的临床缺陷和肺癌不同分子亚型之间的差异，设计构建一种具有多级肿瘤靶向的pH敏感聚合物-PEG-tbFGF纳米载体系统，同时装载紫杉醇和阿司匹林衍生物，将双药协同效应、长循环纳米粒的天然肿瘤靶向、pH敏感的物理化学靶向和tbFGF介导的主动靶向有机结合，实现对高表达FGFR的肺鳞癌组织的特异靶向作用和双药协同抗肿瘤作用。本项目旨在阐明该纳米载体主动靶向肿瘤和智能逐级释药的机制，以及两种化疗药物抗肿瘤信号通路间的对话机制，为提高药物对肺鳞癌的疗效，降低毒副作用提供新方法和新思路。本项目研究结果可为肺鳞癌治疗提供一种理想的靶向载体和联合用药方案，具有较高的研究价值。

根据个体化治疗策略，本项目拟针对小分子抗肿瘤药物现有的临床缺陷，设计构建一种具有多级肿瘤靶向的pH敏感聚合物纳米载体系统，同时装载两种药物，将双药协同效应、长循环纳米粒的被动肿瘤靶向、pH敏感的物理化学靶向有机结合，实现对肿瘤组织的特异靶向作用和双药协同抗肿瘤作用。通过本课题的研究，我们展示了PTX和HS-ASA协同作用提高抗癌疗效，降低毒副作用的对话机制可能主要是由于HS-ASA可以诱导肿瘤细胞凋亡，细胞周期阻滞从而使细胞对PTX的微管抑制作用更加敏感，同时，安全性更高的HS-ASA与PTX联用，可以显著降低PTX的用药剂量从而降低其毒副作用。为阐明两者在蛋白，RNA, 及DNA水平的协同机制，需在今后的研究中继续深入。我们阐明了pH响应型纳米粒在模拟肿瘤细胞内微环境酸碱度（pH=5.0）比正常生理环境（pH=7.4）时释放药物更快，这可能是pH响应型聚合物纳米载体装载的药物在对肿瘤细胞的摄取率更高的主要机制。再次，我们合成了多功能聚合物，构建了一种肿瘤环境响应型（pH敏感）、协同型(可装载两种抗癌药物)的新型肿瘤靶向智能纳米递药系统，建立了pH响应型纳米载体制备技术平台和通过纳米技术同时提高两种难溶性药物水溶性和肿瘤靶向性的技术平台。同时，我们成功建立了一系列独特的转基因斑马移植瘤模型，将在今后的研究中利用此模型研究纳米药物制剂的药效学和毒性评价。受本项目资助，课题组发表标注基金的9篇SCI论文, 申请中国发明专利4项，参加三次国际学术大会交流报告，包括一次特邀口头报告和两次墙报展示，培养硕士研究生4名。