超支化触发式自降解聚合物的设计合成与功能构筑

For conventional dendritic or linear self-immolative polymers, there always exists a major concern that it is not possible to simutaneously combine two key advantages, i.e., facile synthesis and signal amplification capability. To solve the above issue, in this proposal we focus on innovating the design and synthesis of Hyperbranched Self-Immolative Polymers (hSIPs) and their functional applications as drug delivery nanocarriers and ultrasensitive detection and diagnostic systems. By utilizing conventional strategies combining one-pot polycondensation and post-modification, optimizing and screening appropriate building units, we attempt to design and synthesize a series of hSIPs with varying responsive mechanisms and functions through the integration of three types of branching units, four types of triggering entities, and a variety of bioactive reporter residues and targeting moieties. Specifically, we plan to functionalize the periphery of hSIPs with prodrugs via self-immolative linkers and fabricate polyion complexes via reversiable electrostatic interactions between charged hSIPs and biomacromolecules of interest, aiming to achieve programmed release of drugs and biomacromolecles triggered by intracellular or pathological milieu. Specific enzymatic reactions will combined with the intrinsic signal amplification capability of hSIPs to construct positive feedback amplification systems for ultrasensitive detection. Furthermore, we will integrate these positive feedback amplification systems with clinically relevant techniques such as enzyme-linked immunosorbent assay (ELISA) to explore their potential applications in clinical diagnosis and detection. The accomplishment of the above proposed research contents is expected to enrich topological structures and categories of self-immolative polymers, as well as to provide an important reference for the construction of next-generation smart nanocarriers and ultrasensitive detection and diagnostic systems.

针对线型或树枝状触发式自降解聚合物不能兼具信号化学放大和简便合成双重优势的局限性，本申请项目聚焦于触发式自降解超支化聚合物(hSIP)的创新设计与合成，并拓展他们在药物输运载体和超灵敏检测诊断方面的功能应用。采用经典的一锅法缩聚与后修饰策略，优化和筛选构筑基元，设计合成涵盖了多类支化基元、触发基元，以及生物活性报告基元和外围靶向基元的hSIP；拟在hSIP骨架外周通过自降解连接基共价键合前药分子和利用荷电hSIP与生物大分子的静电络合，程序化调控细胞或特征病变组织微环境触发的原药及生物大分子释放；将hSIP固有的化学放大效应与酶促反应相结合，构建正反馈循环放大体系以实现灵敏检测；以此为基础进一步集成hSIP与酶联免疫吸附检测等技术，力图发展用于临床超灵敏检测诊断的新策略。该项目的实施预期将丰富触发式自降解高分子的拓扑结构与类别，为设计新一代智能纳米载体与超灵敏检测诊断功能体系提供重要参考。

在链末端处刺激引发的端基脱除后，触发式自降解聚合物 (SIP) 经历自发的多米诺骨牌式的级联头-尾顺序解聚，形成小分子。在这个项目中，采用一锅法AB2单体的缩聚方法和顺序后功能化，可以轻松制备出具有新型链拓扑结构的水分散型触发式自降解聚合物，超支化自我牺牲聚合物 (hSIPs)。基于hSIP平台，我们探索了非常多的功能，包括靶向和时空控制方式的外周缀合药物的细胞内释放，细胞内递送质粒 DNA 释放，过氧化氢的线粒体靶向荧光检测，检测限低至~20 nM 。为了进一步证明hSIP平台的高效和普适性，将它与酶介导的正反馈循环扩增以及酶联免疫吸附测定 (ELISA) 相结合，用于超灵敏检测病理相关抗原 (例如人类癌胚抗原) 。通过使用双笼闭荧光和异二功能核心分子 (C1) 作为可产生荧光的连接子，构建叠氮化物封端的合成聚合物/成像探针和巯基官能化抗体/蛋白质/肽之间的缀合效率的原位荧光定量。 C1与叠氮基和硫醇官能化前体的正交双“点击”偶联诱导出强荧光的生物缀合物，而 C1 的单“点击”产物基本上保持无荧光。这种“AND”逻辑门型荧光特征还可以进一步与FRET过程集成。项目执行期间，共发表与项目研究内容相关的学术论文5 篇，其中包括第一/通讯作者论文3 篇，分别发表于Angew. Chem. Int. Ed., Macromolecules , Chem. Eur. J.。获授权中国发明专利2项，另外有4项申请中。在3次国际/国内会议中做邀请/分会场报告。