Intracellular delivery of a protein antigen with an endosomal-releasing polymer enhances CD8 T-cell production and prophylactic vaccine efficacy.

Foster S, Duvall CL, Crownover EF, Hoffman AS, Stayton PS
Bioconjug Chem. 2010 21 (12): 2205-12

PMID: 21043513 · PMCID: PMC3075329 · DOI:10.1021/bc100204m

Protein-based vaccines have significant potential as infectious disease and anticancer therapeutics, but clinical impact has been limited in some applications by their inability to generate a coordinated cellular immune response. Here, a pH-responsive carrier incorporating poly(propylacrylic acid) (PPAA) was evaluated to test whether improved cytosolic delivery of a protein antigen could enhance CD8+ cytotoxic lymphocyte generation and prophylactic tumor vaccine responses. PPAA was directly conjugated to the model ovalbumin antigen via reducible disulfide linkages and was also tested in a particulate formulation after condensation with cationic poly(dimethylaminoethyl methacrylate) (PDMAEMA). Intracellular trafficking studies revealed that both PPAA-containing formulations were stably internalized and evaded exocytotic pathways, leading to increased intracellular accumulation and potential access to the cytosolic MHC-1 antigen presentation pathway. In an EG.7-OVA mouse tumor protection model, both PPAA-containing carriers robustly inhibited tumor growth and led to an approximately 3.5-fold increase in the longevity of tumor-free survival relative to controls. Mechanistically, this response was attributed to the 8-fold increase in production of ovalbumin-specific CD8+ T-lymphocytes and an 11-fold increase in production of antiovalbumin IgG. Significantly, this is one of the first demonstrated examples of in vivo immunotherapeutic efficacy using soluble protein-polymer conjugates. These results suggest that carriers enhancing cytosolic delivery of protein antigens could lead to more robust CD8+ T-cell response and demonstrate the potential of pH-responsive PPAA-based carriers for therapeutic vaccine applications.

MeSH Terms (24)

Acrylates Animals Antigen Presentation Antigens Cancer Vaccines CD8-Positive T-Lymphocytes Cell Proliferation Disease-Free Survival Drug Delivery Systems Endosomes Female Hydrogen-Ion Concentration Immunoglobulin G Lymphocyte Activation Methacrylates Mice Mice, Inbred C57BL Neoplasm Transplantation Nylons Ovalbumin Polymers Thymoma Thymus Neoplasms Treatment Outcome

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