基于配位和动态共价键的新型高分子纳米载体用于蛋白质药物的高效负载与控制释放

Polymeric nanocarriers often encounter with problems including low loading capacity & efficiency, and easy drug leakage when they are used to encapsulate protein drugs, leading to low availability, easy inactivation, and short half-life. It has important theoretical significance and great research value to develop new polymeric nanocarriers for solving these problems in protein drug delivery by using of specific interactions between functional groups and proteins. Based on the coordination between the nitrilotriacetic acid (NTA)-chelated zinc ions [Zn(II)] and the imidazole group of histidine residue as well as the formation of two kinds of dynamic covalent bonds including imine linkage and cyclic phenylborate ester between 2-formylbenzeneboronic acid (2-FPBA) and primary amines and/or glycosyls, this project will design and synthesize two kinds of novel polymeric nanocarriers for highly efficient loading and stimuli-responsive release of protein drugs with either histidine imidazole group or lysine ω-amine. The loading capacity & efficiency, stimuli-responsive drug release of protein drugs by the polymeric nanocarriers as well as the change of the protein structure will be systematically studied with insulin and BSA as models. It is expected that novel polymeric nanocarriers will be obtained with properties of highly efficient loading, stimuli-responsive release, and efficient protection of protein drugs.

普通高分子纳米载体用于蛋白质药物投递时往往存在载药量和载药效率低、药物容易泄露等现象，从而导致蛋白质药物利用率低、易失活、半衰期短等问题。利用化学功能基团与蛋白质间的特异相互作用，开发新型高分子纳米载体以解决蛋白质药物投递中的上述问题，具有重要的理论意义和研究价值。本项目拟利用氨三乙酸（NTA）螯合锌离子Zn(II)与组氨酸咪唑基团间的配位作用和2-醛基苯硼酸（2-FPBA）能形成亚胺键和苯硼酸环酯两种动态共价健的特殊性质，分别将表面具有组氨酸咪唑基和赖氨酸ω-氨基的两类蛋白质药物键合到NTA和糖基功能化聚合物上，再通过复合自组装，设计、制备两类新型高分子纳米载体。分别以胰岛素和牛血清蛋白（BSA）为药物模型，系统研究纳米载体的载药量、载药效率、刺激响应性释放行为以及蛋白质药物的结构变化等。优化设计，获得既能够高效负载、刺激响应性释放，又能有效保护蛋白质药物活性的新型高分子纳米载体。

普通纳米药物载体用于蛋白质药物递送时往往存在载药困难、载药量和载药效率低、药物容易泄露等问题。本项目利用化学功能基团与蛋白质药物间的特异相互作用，设计制备了多种高分子纳米药物载体，开展了对蛋白质药物的负载与递送等方面的研究工作，取得了一系列重要研究成果。（1）将自组装复合胶束作为纳米分子伴侣用于胰岛素负载、保护和递送，实现了胰岛素的高效递送和葡萄糖响应性释放，同时有效抑制了胰岛素的聚集，提高了胰岛素稳定性，降低了免疫原性，减少了血液清除；（2）将葡萄糖/过氧化氢双响应纳米凝胶和复合胶束用于胰岛素的递送，既提高了纳米载体的葡萄糖响应性，又有效避免了H2O2产生的毒性；（3）将氨三乙酸/苯硼酸双功能化纳米凝胶和复合胶束用于胰岛素递送，实现了胰岛素的高效负载与葡萄糖响应性控制释放；（4）将葡萄糖响应可注射水凝胶-胶束复合载体用于胰岛素递送，成功模拟了基础和餐时胰岛素分泌，并维持小鼠正常血糖长达24小时；（5）利用自组装纳米分子伴侣成功实现了对胰岛素淀粉样纤维的解聚和对人胰岛淀粉样多肽聚集的有效抑制。本项目为开发新型胰岛素递送体系并应用于糖尿病治疗奠定了重要的理论和技术基础。基于本项目研究工作，已发表基金标注SCI研究论文20篇，申请发明专利11项。

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