Targeted Codelivery of an Antigen and Dual Agonists by Hybrid Nanoparticles for Enhanced Cancer Immunotherapy
| Autor: | Weihang Ji, Xigang Leng, Fan Fan, Linhua Zhang, Yu Qin, Lu Lu, Hongfan Sun, Dunwan Zhu, Chun Wang, Chenlu Huang, Zhiming Zhang, Shengjie Wu, Deling Kong |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
medicine.medical_treatment
Monophosphoryl Lipid A Bioengineering 02 engineering and technology CD8-Positive T-Lymphocytes Cancer Vaccines Mice Immune system Drug Delivery Systems Antigen Cancer immunotherapy Antigens Neoplasm medicine Animals General Materials Science Imiquimod biology Chemistry Mechanical Engineering Toll-Like Receptors General Chemistry TLR7 Dendritic cell Dendritic Cells Neoplasms Experimental 021001 nanoscience & nanotechnology Condensed Matter Physics Immune checkpoint Lipid A Granzyme biology.protein Cancer research Nanoparticles Immunotherapy 0210 nano-technology |
| Zdroj: | Nano letters. 19(7) |
| ISSN: | 1530-6992 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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