Preparation of polymeric Janus particles for stimulation of immune cells

在这项拟议的工作中，将开发用于体内抗原特异性刺激免疫细胞的聚合物纳米颗粒，用于癌症免疫治疗。具体地说，我将制备基于两个隔室的聚丙交酯-乙交酯纳米颗粒，它为结合肿瘤抗原提供一个灵活的支架(第一个隔室)，并释放在塑造免疫反应中重要的细胞因子(第二个隔室)。聚合物Janus粒子将通过电流体动力(EHD)共喷射制备，并将分别对两个隔室进行改性。第一隔室将通过表面嫁接的NHS-酯刷子优化抗原呈递，而第二隔室将优化细胞因子的释放。这种嫁接的聚合物刷子将作为受体分子的灵活载体，触发免疫细胞的抗原特异性激活。嫁接刷子以一种理想的方式将支架的灵活性和多种抗原呈递结合在一起，这两者对于高效的免疫细胞激活都是至关重要的。通过控制刷子的性质(接枝密度、厚度)，可以精确地控制抗原负载量和隔室1的平均距离。细胞因子将被合并到隔室2中，并将通过制备参数调节聚合物的降解速率来控制它们的释放。通过进一步使用两性离子刷子对隔室2进行功能化，将实现粒子在淋巴结(免疫细胞所在的地方)中的长时间滞留。

In the proposed work, polymeric nanoparticles will be developed for in vivo antigen-specific stimulation of immune cells for applications in cancer immunotherapy. Specifically, I will prepare two-compartmental poly(lactide-co-glycolide)-based nanoparticles that provide a flexible scaffold for binding tumor-antigens (compartment 1) and release cytokines that are important in shaping the immune response (compartment 2). Polymeric Janus particles will be prepared by electrohydrodynamic (EHD) co-jetting and the two compartments will be modified individually. Compartment 1 will be optimized for antigen-presentation via surface-grafted NHS-ester brushes whereas compartment 2 will be optimized for cytokine release. The grafted polymer brushes will serve as flexible carriers for receptor molecules which trigger antigen-specific activation of immune cells. Grafted brushes combine flexibility of the scaffold and multiple antigen presentation, both crucial for efficient immune cell activation, in an ideal way. Precise control of antigen loading and average distance in compartment 1 will be achieved by controlling the brush properties (grafting density, thickness). Cytokines will be incorporated into compartment 2 and their release will be controlled by adjusting the degradation rate of the polymer via the preparation parameters. By further functionalizing compartment 2 with zwitterionic brushes, prolonged particle retention in the lymph nodes (where immune cells reside) will be achieved.