Development of a facile strategy to synthesize PLA-based reduction-responsive shell-sheddable nanoassemblies for drug delivery****

目前基于聚合物的纳米药物用于癌症治疗的趋势主要集中在开发具有疏水核的嵌段共聚物纳米组件，使疏水抗癌药物能够被封装。最近，定义明确的嵌段共聚物由疏水性聚乳酸（PLA）和亲水性聚乙二醇（PEG）嵌段组成，目前已在临床实践。然而，传统的系统依赖于扩散控制机制，这种机制是被动的，不受控制的，并且对包膜抗癌药物的释放缓慢。这里的研究机会是探索具有增强/控制药物释放谱的癌症治疗的还原反应降解平台。****在这项拟议的研究中，我们将与位于蒙特利尔的先进聚合物材料（APM）合作，探索一种简单的策略，将二硫键结合到传统设计的PLA-b-PEG嵌段共聚物的设计中。该策略将利用点击型炔-叠氮基环加成反应与开环聚合相结合，合成在PLA和PEG嵌段连接处具有还原反应二硫键（SS）的新型嵌段共聚物，即PLA-SS-PEG嵌段共聚物。重要的参数包括嵌段长度和临近SS键的烷基数量将会改变，以了解结构-性能关系。此外，合成的共聚物将被评估为有效的细胞内药物递送。这个合作项目将为APM提供一个很好的机会，使其在市场上比竞争对手更具竞争力。

Current trend in polymer-based nanomedicine for cancer therapy mainly focuses on the development of block copolymer-based nanoassemblies with hydrophobic cores enabling the encapsulation of hydrophobic anticancer drugs. Recently, well-defined block copolymers consisting of hydrophobic polylactide (PLA) and hydrophilic poly(ethylene glycol) (PEG) blocks have been currently practiced in clinics. However, the conventional systems rely on diffusion-controlled mechanism, which is passive, uncontrolled, and slow for the release of encapsulated anticancer drugs. The research opportunity here is to explore reduction-responsive degradation platform for cancer therapy with enhanced/controlled drug release profile. ****In this proposed research, in collaboration with Advanced Polymeric Materials (APM) located in Montreal, we will explore a facile strategy to incorporate disulfide linkage into the design of conventionally-designed PLA-b-PEG block copolymers. The strategy will utilize a combination of click-type alkyne-azido cycloaddition reaction with ring opening polymerization to synthesize novel block copolymer having a reduction-responsive disulfide linkage (SS) at the junction of PLA and PEG blocks, thus PLA-SS-PEG block copolymers. Important parameters including block lengths and the number of alkyl groups adjacent to SS linkage will be varied to understand the structure-property relationship. Further, the synthesized copolymers will be evaluated for effective intracellular drug delivery. This collaborative project will offer APM a great opportunity to be competitive in markets over their competitors.