智能稳定型细胞内定位输送纳米药物载体的研究

为了实现安全和高效的肿瘤化疗，本研究通过分子设计，将pH响应的苯亚胺键、氧化还原敏感的二硫键、活性羧基和叶酸靶向分子引入生物可降解多嵌段聚氨酯结构中，并使用含有二硫键的小分子对所形成的聚氨酯胶束壳-核界面层进行交联，制备一种智能稳定型细胞内定位输送纳米药物载体，使其实现无毒、可降解、高稳定、长循环、肿瘤靶向、壳卸载、高效细胞内在化、多重刺激响应和药物控制释放等多种功能，并且能够根据需要"开关"部分功能，从而能够将抗癌药物准确、及时、安全地输送到肿瘤细胞内，达到理想的治疗效果。本课题将系统研究这类新型聚氨酯结构与性能之间的关系和科学问题，并探索该智能聚合物胶束功能"开关"对其行为的影响，如交联和解交联对稳定性和药物控释的影响、PEG外壳屏蔽和脱落对靶向和细胞内在化机理的影响等，提供一种具有临床应用潜力的靶向给药系统，并为智能纳米药物载体的设计提供一种新思路和新手段。

To achieve safe and effective cancer chemotherapy, pH-responsive benzoic-imine linkages, redox-sensitive disulfide bonds, reactive carboxyl groups as well as folate ligands are incorporated into the design and preparation of biodegradable multiblock polyurethanes. The polymers self-assemble into nanomicelles, and the interlayer of micelle is chemically cross-linked with disulfide-base agents. In this way, a smart and stable nanocarrier is developed for pinpointed intracellular drug delivery, which exhibits non-toxicity, biodegradability, high stability, long circulation, tumor targeting, shell-detachment, enhanced cell internalization, multistimuli-responsiveness and controlled drug release properties. Moreover, the nanovehicle can "switch on" or "turn off" certain functionalities as required, and can ferry anticancer drugs into tumor cells precisely, timely and safely, thus significantly maximizing the therapeutic efficacy. This research will focus on the structure-property relationship of polyurethanes, and systematically investigate the effects of functional switches, such as crosslinking and shell-detachment, on the stability, drug release kinetics, targeting ability and cellular entry mechanism of multifunctional nanocarriers. This study offers a promising targeted delivery system for cancer therapy, and proposes a new strategy towards the design and fabrication of smart nanomedicines.