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ACS Biomater Sci Eng. 2017 Feb 13;3(2):179-194. doi: 10.1021/acsbiomaterials.6b00408. Epub 2016 Nov 9.

Fatty Acid-Mimetic Micelles for Dual Delivery of Antigens and Imidazoquinoline Adjuvants.

Author information

1
Department of Chemical and Biomolecular Engineering, Vanderbilt University, 2400 Highland Avenue.
2
Department of Biomedical Engineering, Vanderbilt University, 2301 Vanderbilt Place.
3
Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Medical Center North.
4
Department of Veterans Administration Tennessee Valley Healthcare System, 1310 24th Avenue South.
5
Vanderbilt Center for Immunobiology, Vanderbilt University Medical Center, 2301 Vanderbilt Place, Nashville, TN 37235, USA.

Abstract

Vaccine design has undergone a shift towards the use of purified protein subunit vaccines, which offer increased safety and greater control over antigen specificity, but at the expense of immunogenicity. Here we report the development of a new polymer-based vaccine delivery platform engineered to enhance immunity through the co-delivery of protein antigens and the Toll-like receptor 7 (TLR7) agonist imiquimod (IMQ). Owing to the preferential solubility of IMQ in fatty acids, a series of block copolymer micelles with a fatty acid-mimetic core comprising lauryl methacrylate (LMA) and methacrylic acid (MAA), and a poly(ethylene glycol) methyl ether methacrylate (PEGMA) corona decorated with pyridyl disulfide ethyl methacrylate (PDSM) moieties for antigen conjugation were synthesized via reversible addition-fragmentation chain transfer (RAFT) polymerization. Carriers composed of 50 mole% LMA (LMA50) demonstrated the highest IMQ loading (2.2 w/w%) and significantly enhanced the immunostimulatory capacity of IMQ to induce dendritic cell maturation and proinflammatory cytokine production. Conjugation of a model antigen, ovalbumin (OVA), to the corona of IMQ-loaded LMA50 micelles enhanced in vitro antigen uptake and cross-presentation on MHC class I (MHC-I). A single intranasal (IN) immunization of mice with carriers co-loaded with IMQ and OVA elicited significantly higher pulmonary and systemic CD8+ T cell responses and increased serum IgG titer relative to a soluble formulation of antigen and adjuvant. Collectively, these data demonstrate that rationally designed fatty acid-mimetic micelles enhance intracellular antigen and IMQ delivery and have potential as synthetic vectors for enhancing the immunogenicity of subunit vaccines.

KEYWORDS:

Imiquimod; RAFT polymerization; Toll-like receptor 7; block copolymer micelles; mucosal immunity; subunit vaccine

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