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发展趋势主要集中在以嵌段共聚物为基础的具有疏水核的纳米组装体的开发，从而使疏水性抗癌药物能够被包裹。最近，由疏水性聚乳酸(PLA)和亲水性聚乙二醇(PEG)嵌段组成的定义明确的嵌段共聚物目前已在临床上得到应用。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、包囊抗癌药物释放缓慢的。这里的研究机会是探索具有增强/受控药物释放轮廓的癌症治疗的还原响应性降解平台。*在这项拟议的研究中，我们将与蒙特利尔的先进聚合物材料公司(APM)合作，探索一种简便的策略，将二硫键结合到传统设计的解放军-b-聚乙二醇嵌段共聚物的设计中。该策略将利用点击式的炔-叠氮环加成反应和开环聚合相结合的方法合成新型嵌段共聚物，该嵌段共聚物在聚乳酸和聚乙二醇嵌段的交界处具有还原响应性的二硫键(SS)，从而得到聚乳酸-聚乙二醇单嵌段共聚物。重要的参数，包括链段长度和与SS键相邻的烷基数量将发生变化，以了解结构与性质的关系。此外，合成的共聚物将被评估为有效的细胞内药物输送。这一合作项目将为APM提供一个极好的机会，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.