Dendritic Cell-Targeted Nanovaccine Delivery System Prepared with an Immune-Active Polymer

Abstract

Targeting dendritic cells (DCs), either ex vivo (Ex. Sipuleucel-T) or in vivo, for stimulating cellular immunity has been a leading approach for cancer vaccines. We have rationally engineered a nanoparticle (NP)-based delivery system for vaccines (InAc-NPs) using inulin acetate (InAc) as the polymer to target DCs. The material and the antigen-encapsulated InAc-NPs (∼190 nm in diameter) were characterized for their physicochemical properties. As a potent vaccine adjuvant, InAc-NPs activated TLR4 on multiple immune cells, including DCs and primary swine and human cells, to secrete various cytokines as detected by enzyme-linked immunosorbent assay and quantitative polymerase chain reaction. In addition, InAc-NPs promoted the maturation of DCs as observed by a decreased phagocytic ability and enhanced capability to activate various maturation markers (MHC-I, MHC-II, CD40, and CD80) quantified using flow cytometry. In mice, the InAc-NPs produced strong serum antibody titers (total IgG, IgG1, and IgG2a) against the encapsulated antigen (ovalbumin) similar to complete Freund's adjuvant. Additionally, as a dose-sparing delivery system, antigen delivered through InAc-NPs generated higher antibody titers (IgG1, 1.57 times; IgG-total, 1.66 times; and IgG2a, 29.8 times) even at 100 times less antigen dose. High amounts of cytokines representing both humoral (IL4 and IL10) and cell-mediated (IL2 and IFN-γ) immunities were secreted from splenocytes of mice immunized with InAc-NPs. Importantly, InAc-NPs provided complete protection in 100% of the vaccinated mice from metastasis of intravenously injected melanoma cells (B₁₆-F₁₀) to lungs. In addition, the InAc-NPs were cleared from the injection site within 30 h of injection (in vivo imaging) and displayed no toxicity at the injection site (histology). The current study demonstrates that the multifunctional InAc-based nanovaccine delivery system has potential applications in cancer immunotherapy and delivering vaccines against various infectious diseases.

Keywords: cancer immunotherapy; dendritic cell targeting; humoral and cellular immunity; inulin acetate; nanoparticulate vaccine; toll-like receptor-4 agonists.