Department of Bioengineering, University of Washington, Seattle, WA, 98195, USA.
Adv Healthc Mater. 2022 May;11(9):e2101651. doi: 10.1002/adhm.202101651. Epub 2021 Nov 7.
Peptide-based cancer vaccines offer production and safety advantages but have had limited clinical success due to their intrinsic instability, rapid clearance, and low cellular uptake. Nanoparticle-based delivery vehicles can improve the in vivo stability and cellular uptake of peptide antigens. Here, a well-defined, self-assembling mannosylated polymer is developed for anticancer peptide antigen delivery. The amphiphilic polymer is prepared by reversible addition-fragmentation chain transfer (RAFT) polymerization, and the peptide antigens are conjugated to the pH-sensitive hydrophobic block through the reversible disulfide linkage for selective release after cell entry. The polymer-peptide conjugates self-assemble into sub-100 nm micelles at physiological pH and dissociate at endosomal pH. The mannosylated micellar corona increases the accumulation of vaccine cargoes in the draining inguinal lymph nodes and facilitates nanoparticle uptake by professional antigen presenting cells. In vivo studies demonstrate that the mannosylated micelle formulation improves dendritic cell activation and enhances antigen-specific T cell responses, resulting in higher antitumor immunity in tumor-bearing mice compared to free peptide antigen. The mannosylated polymer is therefore a simple and promising platform for the delivery of peptide cancer vaccines.
基于肽的癌症疫苗具有生产和安全性优势，但由于其内在的不稳定性、快速清除和低细胞摄取率，临床应用效果有限。基于纳米颗粒的递药载体可以提高肽抗原的体内稳定性和细胞摄取率。本文开发了一种结构明确的、自组装的甘露糖化聚合物用于抗癌肽抗原递药。该两亲性聚合物通过可逆加成-断裂链转移（RAFT）聚合制备，肽抗原通过可逆二硫键连接到 pH 敏感的疏水性嵌段上，在细胞内进入后进行选择性释放。聚合物-肽缀合物在生理 pH 下自组装成小于 100nm 的胶束，在内涵体 pH 下解离。甘露糖化胶束冠增加了疫苗货物在引流腹股沟淋巴结中的积累，并促进了专业抗原呈递细胞对纳米颗粒的摄取。体内研究表明，甘露糖化胶束制剂可改善树突状细胞的激活，并增强抗原特异性 T 细胞反应，与游离肽抗原相比，在荷瘤小鼠中产生更高的抗肿瘤免疫。因此，甘露糖化聚合物是一种简单而有前途的肽类癌症疫苗递药平台。
