Tianjin Key Laboratory of Biomedical Materials , Institute of Biomedical Engineering, Chinese Academy of Medical Sciences & Peking Union Medical College , Tianjin 300192 , China.
Department of Biomedical Engineering , University of Minnesota , 7-116 Hasselmo Hall, 312 Church Street SE , Minneapolis , Minnesota 55455 , United States.
Nano Lett. 2019 Jul 10;19(7):4237-4249. doi: 10.1021/acs.nanolett.9b00030. Epub 2019 Mar 21.
Among approaches of current cancer immunotherapy, a dendritic cell (DC)-targeted vaccine based on nanotechnology could be a promising way to efficiently induce potent immune responses. To enhance DC targeting and vaccine efficiency, we included imiquimod (IMQ), a toll-like receptor 7/8 (TLR 7/8) agonist, and monophosphoryl lipid A (MPLA), a TLR4 agonist, to synthesize lipid-polymer hybrid nanoparticles using PCL-PEG-PCL and DOTAP (IMNPs) as well as DSPE-PEG-mannose (MAN-IMNPS). The spatiotemporal delivery of MPLA (within the outer lipid layer) to extracellular TLR4 and IMQ (in the hydrophobic core of NPs) to intracellular TLR7/8 can activate DCs synergistically to improve vaccine efficacy. Ovalbumin (OVA) as a model antigen was readily absorbed by positively charged DOTAP and showed a quick release . Our results demonstrated that this novel nanovaccine enhanced cellular uptake, cytokine production, and maturation of DCs. Compared with the quick metabolism of free OVA-agonists, the depot effect of OVA-IMNPs was observed, whereas MAN-OVA-IMNPs promoted trafficking to secondary lymphoid organs. After immunization with a subcutaneous injection, the nanovaccine, especially MAN-OVA-IMNPs, induced more antigen-specific CD8 T cells, greater lymphocyte activation, stronger cross-presentation, and more generation of memory T cells, antibody, IFN-γ, and granzyme B. Prophylactic vaccination of MAN-OVA-IMNPs significantly delayed tumor development and prolonged the survival in mice. The therapeutic tumor challenge indicated that MAN-OVA-IMNPs prohibited tumor progression more efficiently than other formulations, and the combination with an immune checkpoint blockade further enhanced antitumor effects. Hence, the DC-targeted vaccine codelivery with IMQ and MPLA adjuvants by hybrid cationic nanoparticles in a spatiotemporal manner is a promising multifunctional antigen delivery system in cancer immunotherapy.
在当前癌症免疫疗法中，基于纳米技术的树突状细胞（DC）靶向疫苗可能是一种有效诱导强烈免疫反应的有前途的方法。为了增强 DC 靶向性和疫苗效率，我们将咪喹莫特（IMQ），一种 Toll 样受体 7/8（TLR 7/8）激动剂，和单磷酰脂质 A（MPLA），一种 TLR4 激动剂，纳入到使用 PCL-PEG-PCL 和 DOTAP（IMNPs）以及 DSPE-PEG-甘露糖（MAN-IMNPS）合成的脂-聚合物杂化纳米粒子中。MPLA（在外部脂质层内）向细胞外 TLR4 和 IMQ（在 NPs 的疏水性核心内）向细胞内 TLR7/8 的时空递呈可以协同激活 DC，从而提高疫苗效率。卵清蛋白（OVA）作为一种模型抗原，很容易被带正电荷的 DOTAP 吸收，并迅速释放。我们的结果表明，这种新型纳米疫苗增强了 DC 的细胞摄取、细胞因子产生和成熟。与游离 OVA-激动剂的快速代谢相比，观察到 OVA-IMNPs 的储存效应，而 MAN-OVA-IMNPs 促进了向二级淋巴器官的转运。通过皮下注射免疫后，纳米疫苗，特别是 MAN-OVA-IMNPs，诱导了更多的抗原特异性 CD8 T 细胞、更大的淋巴细胞激活、更强的交叉呈递以及更多的记忆 T 细胞、抗体、IFN-γ和颗粒酶 B 的产生。MAN-OVA-IMNPs 的预防性疫苗接种显著延缓了肿瘤的发展并延长了小鼠的存活时间。治疗性肿瘤挑战表明，MAN-OVA-IMNPs 比其他制剂更有效地阻止肿瘤进展，与免疫检查点阻断的联合进一步增强了抗肿瘤作用。因此，通过时空混合阳离子纳米粒子共递送 DC 靶向疫苗和 IMQ 和 MPLA 佐剂是癌症免疫治疗中一种有前途的多功能抗原递送系统。
