Tongji School of Pharmacy, Huazhong University of Science and Technology, Wuhan, Hubei, China.
Department of Gynecologic Oncology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, Hubei, China.
Nanomedicine. 2019 Nov;22:102092. doi: 10.1016/j.nano.2019.102092. Epub 2019 Oct 5.
Dendritic cell (DC)-targeted vaccines based on nanotechnology are a promising strategy to efficiently induce potent immune responses. We synthesized and manufactured a mannose-modified poly (β-amino ester) (PBAE) nano-vaccines with easily tuneable and pH-sensitive characteristics to co-deliver the tumor-associated antigen polypeptide Trp-2 and the TLR4 agonist monophosphoryl lipid A (MPLA). To reduce immunosuppression in the tumor microenvironment, an immune checkpoint inhibitor, PD-L1 antagonist, was administrated along with PBAE nano-vaccines to delay melanoma development. We found that mannosylated Trp-2 and MPLA-loaded PBAE nano-vaccines can target and mature DCs, consequently boosting antigen-specific cytotoxic T lymphocyte activity against melanoma. The prophylactic study indicates that combination therapy with PD-L1 antagonist further enhanced anti-tumor efficacy by 3.7-fold and prolonged median survival time by 1.6-fold more than free Trp-2/MPLA inoculation. DC-targeting PBAE polymers have a great potential as a nanotechnology platform to design vaccines and achieve synergistic anti-tumor effects with immune checkpoint therapy.
基于纳米技术的树突状细胞（DC）靶向疫苗是一种很有前途的策略，可以有效地诱导有效的免疫反应。我们合成并制造了具有易于调节和 pH 敏感性的甘露糖修饰的聚（β-氨基酯）（PBAE）纳米疫苗，以共同递送肿瘤相关抗原多肽 Trp-2 和 TLR4 激动剂单磷酰脂质 A（MPLA）。为了减少肿瘤微环境中的免疫抑制，我们与 PBAE 纳米疫苗一起给予免疫检查点抑制剂 PD-L1 拮抗剂，以延缓黑色素瘤的发展。我们发现，甘露糖化的 Trp-2 和 MPLA 负载的 PBAE 纳米疫苗可以靶向并成熟 DC，从而增强针对黑色素瘤的抗原特异性细胞毒性 T 淋巴细胞活性。预防性研究表明，与游离 Trp-2/MPLA 接种相比，联合使用 PD-L1 拮抗剂可将抗肿瘤疗效提高 3.7 倍，并将中位生存时间延长 1.6 倍。靶向 DC 的 PBAE 聚合物具有作为纳米技术平台设计疫苗的巨大潜力，并与免疫检查点治疗实现协同抗肿瘤作用。
