抗肿瘤多药耐药性及pH响应性肿瘤微环境靶向纳米给药系统成为抗肿瘤研究热点。申请者前期研究发现聚乙烯亚胺（PEI）与吲哚美辛（IND）及难溶性药物之间通过氢键、静电、疏水作用自组装构建具有高载药性稳定的口服纳米给药系统，由于PEI注射后生物相容性低，该纳米给药系统注射前景黯淡。基于前期研究本项目拟设计合成基于席夫碱结构的可pH响应性清除聚乙二醇（PEG）链的PEG-Sc-PEI共聚物，选取多烯紫杉醇（DTX）为模型药物，通过PEG-Sc-PEI与IND及DTX之间的多重非共价键作用力自组装构建具有pH响应性清除PEG链的高载药性肿瘤微环境靶向纳米药物递送系统，并利用IND抗肿瘤多药耐药性，实现基于智能pH响应性的多功能肿瘤微环境靶向及抗肿瘤多药耐药性纳米药物递送系统的构建。课题的顺利执行不仅能为DTX提供新的递送载体方式，亦能为构建细胞毒性药物的肿瘤靶向及抗肿瘤多药耐药性递送提供一条新思路。

Nano drug delivery system based on pH-responsive which both target tumor cells and reverse tumor multidrug resistance have been incressing hotspots in anti-tumor research field. Our previous studies have found a new routine to fabricate oral nano-drug delivery system with high drug loading via non-covalent interactions like hydrophobic, electrostatic, and hydrogen bonding forces between polyethylene imine(PEI)，indomethacin(IND) and various hydrophobic drugs . Unfortunately, Limited by the poor biocompatibility of PEI, the formulation above is difficult to be intravenous injected. Based on past studies, we plan to design and synthesis pH responsive cleavable PEGlated PEI based on Schiff base, and fabricate pH-responsive PEG cleavable nanoassemblies via multiple non-covalent interactions between PEI, IND and docetaxel(DTX), which can efficiently target tumor microenvironment by pH-response and overcome tumor multidrug resistance by IND. According to successful fabricating, this project will provide new insights into the design of novel docetaxel or other lipophilic anti-tumor therapeutics delivery system, Furthmore, it also opens a new approach for the self-assembly of tumor targeted drug delivery system.

摘要：抗肿瘤多药耐药性及pH响应性肿瘤微环境靶向纳米给药系统已成为抗肿瘤研究中的广受研究者关注的热点。受助于国家自然基金的支持,本课题设计并合成基于席夫碱结构的可pH响应性清除聚乙二醇（PEG）链的PEG-s-PEI共聚物，通过其与吲哚美辛（IND）之间氢键作用、pi-pi堆积作用与疏水作用共同自组装,成功负载了多烯紫杉醇与紫杉醇等抗肿瘤药物。该给药系统为3层结果，最外层为PEG链，内壳为聚乙烯亚胺与吲哚美辛组成，而核心为紫杉醇等疏水药物。在肿瘤微环境中，PEG链基于pH响应性脱落，从而提高纳米粒表面电位，增加肿瘤细胞的摄取效率，达到肿瘤靶向作用。进入肿瘤细胞后，由于吲哚美辛与疏水药物的分布不同，吲哚美辛首先释放以降低肿瘤细胞的耐药作用，帮助后续释放的紫杉醇在细胞内的保留时间。体内外结果表面，该纳米系统可显著提高紫杉醇与多西紫杉醇的抗肿瘤活性，并降低细胞的多药耐药性。