Preventative Vaccine-Loaded Mannosylated Chitosan Nanoparticles Intended for Nasal Mucosal Delivery Enhance Immune Responses and Potent Tumor Immunity

Abstract

Chitosan (CS) has been extensively used as a protein drug and gene delivery carrier, but its delivery efficiency is unsatisfactory. In this study, a mannose ligand was used to modify CS, which could enhance the delivery efficiency of CS via mannose receptor-mediated endocytosis. A preventative anti-GRP DNA vaccine (pCR3.1-VS-HSP65-TP-GRP6-M2, pGRP) was condensed with mannosylated chitosan (MCS) to form MCS/pGRP nanoparticles. Nanoparticles were intranasally administered in a subcutaneous mice prostate carcinoma model to evaluate the efficacy on inhibition of the growth of tumor cells. The titers of anti-GRP IgG that lasted for 11 weeks were significantly higher than that for administration of CS/pGRP nanoparticles (p < 0.01) and intramuscular administration of a pGRP solution (p < 0.05) to mice. In addition, immunization with MCS/pGRP nanoparticles could suppress the growth of tumor cells. The average tumor weight (0.79 ± 0.30 g) was significantly lower than that in the CS/pGRP nanoparticle group (1.69 ± 0.15 g) (p < 0.01) or that in the pGRP group (1.12 ± 0.37 g) (p < 0.05). Cell binding and cellular uptake results indicated that MCS/pGRP nanoparticles bound with C-type lectin receptors on macrophages. MCS was an efficient targeting gene delivery carrier and could be used in antitumor immunotherapy.

Low Molecular Weight Chitosan (LMWC)-based Polyplexes for pDNA Delivery: From Bench to Bedside

“…More recently, mannosylated Ch nanoparticles have been administered by the nasal mucosa route to elicit serum anti-GFP IgG anitibodies and inhibit the growth of gastrin-releasing peptide (GRP) dependent tumor cells. The results confirmed that these Ch based carriers are feasible in DNA vaccine delivery and they offer a possibility for efficient tumor immunotherapy [94].…”

Modification of Asparagine-Linked Glycan Density for the Design of Hepatitis B Virus Virus-Like Particles with Enhanced Immunogenicity

“…Targeting the mannose receptor, a C-type lectin, showed that mannosylation provided an efficient strategy to improve antigen uptake, processing, and presentation. Mannosylation enhanced uptake of VLPs by antigen-presenting cells (38), and also enhanced the cell-mediated and humoral immunogenicity of immunogens (40,(45)(46)(47). Mannosylated solid lipid nanoparticles loaded with HBsAg induced stronger cellular responses than nanoparticles devoid of mannose (48).…”

Micro- and nanoparticulates for DNA vaccine delivery

“…Mannose functionalization of chitosan increases nanoparticle association with APCs and increases internalization via mannose receptor-mediated endocytosis. [46][47][48] Layek et al 49 developed an L-phenylalanine-modified chitosan for increased adsorptive endocytosis and intracellular dissociation of DNA, further functionalized with mannose for APC-specific targeting (Man-CS-Phe/DNA). Following intradermal delivery of Man-CS-Phe/DNA complexes encoding hepatitis B surface antigen (HBsAg) to mice, high anti-HBsAg titers were observed for up to six weeks, as well as increased lymphocyte proliferation and increased IL-4 and IFN-g production.…”