基于双重响应聚合物胶束的抗肿瘤主动靶向给药系统

在肿瘤治疗研究中，如何提高抗肿瘤药物的输送效率从而提高药物的治疗效果是目前药物载体研究的一个最主要挑战。在本项目中，我们将针对纳米载体从血液循环到释放药物进入细胞核所要经历的多种生理屏障，设计一种具有pH梯度响应和氧化还原响应的双重响应聚合物靶向胶束。我们期望这种新型胶束载体具备以下特征：（1）在血液循环中能保持高度稳定性；（2）当其穿透进入肿瘤组织后能灵敏地响应pH值变化实现从负电到正电的电荷反转，从而通过主动靶向和静电作用提高肿瘤细胞对纳米载体的吞噬量；（3）在细胞内，载体再次精确地响应溶酶体中更低的pH值并通过质子海绵效应迅速逃离溶酶体，然后在谷胱甘肽还原下使胶束聚合物链中的二硫键断裂，胶束解体，将药物迅速释放到细胞核内。我们将从细胞生物学和分子水平上揭示纳米载体与亚细胞结构的作用机理，构建出对恶性肿瘤有优异治疗效果而对正常组织低毒性的新型靶向纳米给药系统。

Efficient delivery of therapeutic agent with nanocarriers into nucleus to achieve high therapeutic efficiency is still a major challenge for cancer therapy. In this study, we will develop a dual-responsive polymer micelle system with sheddable polyethyleneimine (PEI) shells for actively targeted drug delivery to overcome mucosal barriers, nonspecific uptake and intracellular drug-resistance. We anticipate that the micelle system holds such advantages: (1) a long blood circulation; (2) an ultrasensitive negative-to-positive charge reversal in response to the extracellular pH value, which results in greatly enhanced uptake by cancer cells via electrostatic interaction; (3) once the micelles located in the lysosomes, the disulfide linkages can be cleaved by GSH in cytoplasm and in turn the hydrophilic PEI shell is deshielded, leading to the rapid release of the encapsulated agent into the nuclei. We will reveal the interaction mechanism between nanocarriers and subcellular structure from both cell biology and molecular level, and construct a novel targeted nanoparticle drug delivery system with high therapeutic efficacy against solid tumor but low toxicity to normal tissues.