Targeted Codelivery of an Antigen and Dual Agonists by Hybrid Nanoparticles for Enhanced Cancer Immunotherapy

• Published in: Nano letters 2019-07, Vol.19 (7), p.4237-4249
• Main Authors: Zhang, Linhua, Wu, Shengjie, Qin, Yu, Fan, Fan, Zhang, Zhiming, Huang, Chenlu, Ji, Weihang, Lu, Lu, Wang, Chun, Sun, Hongfan, Leng, Xigang, Kong, Deling, Zhu, Dunwan
• Format: Article
• Language: English
• Subjects: Animals; Antigens, Neoplasm - immunology; Antigens, Neoplasm - pharmacology; Cancer Vaccines - immunology; Cancer Vaccines - pharmacokinetics; Cancer Vaccines - pharmacology; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - pathology; Dendritic Cells - immunology; Dendritic Cells - pathology; Drug Delivery Systems; Imiquimod - immunology; Imiquimod - pharmacokinetics; Imiquimod - pharmacology; Immunotherapy; Lipid A - analogs & derivatives; Lipid A - immunology; Lipid A - pharmacokinetics; Lipid A - pharmacology; Mice; Nanoparticles; Neoplasms, Experimental - immunology; Neoplasms, Experimental - pathology; Neoplasms, Experimental - therapy; Toll-Like Receptors - agonists; Toll-Like Receptors - immunology
• ISSN: 1530-6984; 1530-6992
• DOI: 10.1021/acs.nanolett.9b00030

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 in vitro. 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.