Abstract

Cancer vaccines have been developed as an additional method of treatment in the fight against cancer. However, an important barrier to an effective vaccine is the inefficient presentation of exogenous antigen by dendritic cells to cytotoxic CD8 T cells. In this study, DPPC liposomes were modified with channels and loaded with polyethyleneimine (PEI) and 5,6-dimethylxanthenone-4-acetic acid (DMXAA) to produce a vaccine carrier. The liposomes were designed to be pH responsive to facilitate delivery of antigens directly to the cytoplasm of antigen presenting cells, bypassing the cross-presentation pathway and improving cellular immune responses. The lysis of liposomes in acidic cell-free conditions was measured using a validated dynamic light scattering assay in order to gain an insight into the mechanism of PEI-mediated lysis. Dendritic cell stimulation and T cell proliferation was investigated in vitro and the potential of this formulation to stimulate a therapeutic anti-cancer immune response was examined in a murine melanoma model. The modified formulation stimulated T cell activation in vitro and induced a small but significant increase in survival in immunized mice. Overall, liposomes modified with PEI and channels successfully delivered antigen to the cytoplasm of dendritic cells, which subsequently led to the development of an appropriate immune response.

摘要

癌症疫苗已被开发为对抗癌症的另一种治疗方法。然而，有效疫苗的一个重要障碍是树突状细胞无法有效地将外源抗原呈递给细胞毒性 CD8 T 细胞。在本研究中，DPPC 脂质体经过通道修饰并负载聚乙烯亚胺 (PEI) 和 5,6-二甲基呫吨酮-4-乙酸 (DMXAA) 以生产疫苗载体。脂质体被设计成具有pH响应性，以促进抗原直接递送至抗原呈递细胞的细胞质，绕过交叉呈递途径并改善细胞免疫反应。为了深入了解 PEI 介导的裂解机制，使用经过验证的动态光散射测定法测量了在酸性无细胞条件下脂质体的裂解。在体外，并在小鼠黑色素瘤模型中检查了该制剂刺激治疗性抗癌免疫反应的潜力。改良的配方在体外刺激了 T 细胞活化，并诱导免疫小鼠的存活率小幅但显着增加。总体而言，用 PEI 和通道修饰的脂质体成功地将抗原递送到树突状细胞的细胞质中，从而导致产生适当的免疫反应。