具有多重刺激响应性的蛋白质–聚合物–稀土杂化荧光纳米凝胶的构建与性能研究

Theranostics is a treatment strategy that combines diagnostics with therapeutics. Recently, nanogel as a nanocarrier for loading therapeutic drugs and diagnostic reagents has attracted much attention due to the unique properties of high drug loading efficiency and controlled release. The multifunctional nanogels with multiple stimulus responsive properties and fluorescence characteristics can not only transport the drugs to targeted site, but also realize the real-time monitoring of tumor treatment through autofluresence properties. However, how to easily synthesize multifunctional nanogels with high biocompatibility and fluorescence remains a challenge. In this project, protein-polymer-rare earth hybrid fluorescent nanogel will be prepared in situ via polymerization-induced self-assembly or polymerization-induced thermal self-assembly in aqueous solution. The effects of monomers, cross-linking agents, rare earth organic ligands and proteins on the size, stability and luminescent properties of nanogels will be investigated in detail. The impacts of the different external stimuli (temperature or reducing agent) on the dissociation and drug-controlled release of nanogel will also be discussed. In addition, the toxicity and cellular uptake of nanogel will be investigated and a multifunctional nanocarrier with imaging, drug delivery and treatment will be constructed. The research is expected to provide new ideas and theoretical basis for the design and development of multifunctional nanogel.

诊断治疗学是将诊断学与治疗学结合起来的一种治疗策略。近年来，由于具有很高的药物装载效率和可控释放等优点，纳米凝胶作为同时装载治疗药物和诊断试剂的载体而备受关注。具有多重刺激响应性和荧光特性的多功能纳米凝胶，不仅能响应外界的刺激将药物定向输送到病灶部位，而且可通过载体本身的发光特性实现肿瘤治疗的实时监控。但如何简便地合成具有较高生物相容性和荧光性能的多功能纳米凝胶仍然是一个挑战。本项目拟采用聚合诱导自组装或者聚合诱导热自组装的方法，在水溶液中原位制备蛋白质–聚合物–稀土杂化荧光纳米凝胶。系统研究单体、交联剂、稀土有机配体和蛋白质等因素，对纳米凝胶尺寸、稳定性、发光性能的影响，探讨不同的外界刺激（温度或还原剂）下，纳米凝胶的解离和药物控制释放情况。研究纳米凝胶的毒性与细胞摄取情况，构建集成像、药物输送和治疗于一体的多功能纳米载体。该研究有望为多功能纳米凝胶的设计与研发提供新的思路和理论依据。

多功能（纳米）水凝胶在许多领域，如组织工程、细胞封装、药物输送、传感器和生物电子学等，显示出广泛的应用。本项目主要围绕蛋白质-聚合物-稀土杂化（纳米）水凝胶的设计、合成，发光性能，刺激响应性和生物相容性等方面开展研究工作。主要包括：（1）设计合成了两种双功能型的稀土有机配体，利用与巯基相关的类迈克尔加成和芳香亲核取代反应，制备了两种聚合物基和蛋白质基稀土杂化发光水凝胶。探索了制备水凝胶的条件，研究了其发光性能、机械性能和生物相容性。（2）利用蛋白质上的氨基与聚合物上的碳酸酯基团的反应，合成了一种具有温度/氧化还原响应性的蛋白质-聚合物纳米水凝胶，详细探讨了纳米水凝胶的相变温度和氧化还原响应性，并研究了其催化活性和细胞毒性。（3）合成了四种有机小分子配体，研究了它们在锌离子、铜离子和有机溶剂中的含水量检测方面的应用。本项目在多功能（纳米）水凝胶的设计、合成方面提供了大量的实验数据，有望为新型发光生物材料的设计与研发提供新的思路。