内部串级修饰功能集合型树状大分子的构建及其应用于抗癌药物输送

Dendrimer with precise 3D nanosized molecular structure provide a perfect platform for anticancer drug carrier, which is promising in clinical. Multi-functionalization is the key to improve the drug delivery efficiency of dendrimer-based nanomedicines. Currently, dendrimers are usually surface functionalized with multiple agents, which has the following drawbacks: 1. It sacrifices the unique feature of dendrimers, that is, the preciseness of their molecular structure, because the high amount of functional groups with the same reactivity make it impossible to precisely control the number and the position of the functional groups; 2. The functional groups, such as hydrophobic drug and fluorescent probes, anchored on the dendrimer periphery can interact with blood components, thereby altering the pharmacokinetics; 3. The limited functionalization on dendrimer periphery cannot fully meet the requirements for overcome the multiple biological barriers during delivery and thus cannot improve drug efficacy. To solve these problems, based on preliminary work, we propose to develop interior cascade functionalized dendrimers through generation-by-generation introducing functional moieties as dendrimer-building blocks including drug-binding ligands, drug or imaging molecules, environment-sensitive chemical bonds or groups. Such interior cascade functionalized dendrimers possess precise structure and also capable to functionalized with favorable properties such as high drug loading content, enhanced drug stability, controlled release properties, improved pharmacokinetics, enhanced tumor accumulation and anticancer activity. We aim to improve the drug delivery efficiency of dendrimer-based cancer nanomedicines through cascade functionalization both interior and exterior.

树状大分子因其精准的三维结构是优异的抗癌药物载体，具有良好的临床应用前景，部分已经进入不同临床试验阶段。多功能化是改善树状大分子药物输送能力的关键，但是传统的功能化集中在对大分子表面的修饰，主要存在以下问题：1.表面引入不同数量的功能基团破坏了大分子的精准结构；2.表面功能基团易与血液蛋白发生非特异性作用从而影响大分子的药动学性质；3.表面有限的功能化，无法实现高效药物输送。本项目拟在树状大分子内部引入单一或集成化的功能基团（如活性药物分子、与药物分子具有强相互作用的基团、微环境响应性基团等），精准合成内部功能化的结构单一可控的树状大分子，实现药物分子的特异性包载并调控药物释放速率，获得稳定的药动学性质，提高药物肿瘤输送效率和抗肿瘤效果。本研究创新性地将功能集成化引入到树状大分子的内部结构中，为树状大分子的多功能化提供了新的思路，对于推进树状大分子载体的生物应用具有重要的意义。

树状大分子因其精准的三维结构是优异的抗肿瘤药物载体，具有良好的临床应用前景，部分已经进入不同临床试验阶段。多功能化是改善树状大分子药物输送能力的关键，但是传统的功能化集中在对大分子表面的无选择性修饰，破坏了大分子的精准结构，影响大分子药动学，无法实现高效药物递送，临床转化困难。.在基金委面上项目（NO.21875211）四年的资助下，项目负责人提出了以荧光染料、药物分子或（和）其他活性分子为内部结构单元构建功能化树状大分子的通用方法，通过分子设计和精准化学合成获得了一系列分子级精准的荧光染料纳米探针、环境响应树状大分子药物载体和树状大分子药物偶联物，揭示了功能化树状大分子的尺寸、结构依赖的物理化学性质和机制，初步阐明了树状大分子结构与药物释放行为、肿瘤富集、肿瘤渗透和抗肿瘤性能的构效关系，为开发具有高抗肿瘤疗效的树状大分子纳米药物提供了依据，并为新型抗肿瘤纳米诊疗药物的设计提供了新的思路。.在四年中，以通讯作者在国内外学术期刊发表相关研究工作论文23篇，其中SCI影响因子大于10的15篇，（包括Angewandte Chemie-International Edition 1篇，Advanced Materials 1篇，Advanced Functional Materials 4篇，ACS Nano 2篇，Journal of Controlled Release 3篇，Small 1篇，ACS Applied Materials & Interfaces 2篇，Advanced Drug Delivery Reviews 1篇），国内重要期刊论文4篇，相关技术获批专利5项，并已开展与制药企业合作的后续转化工作。项目负责人受邀在多个国内外会议上做邀请报告，获教育部青年长江学者称号（2020年），获浙江省自然科学一等奖1项（排名第3）。