Conjugation of a Small Molecule TLR7 Agonist to Silica Nanoshells Enhances Adjuvant Activity

Stimulation of toll-like receptors (TLRs) and/or NOD-like receptors (NLRs) on immune cells initiates and directs antigen-specific immune responses that are essential for vaccine adjuvants. The small molecule TLR7 agonist, imiquimod, has been approved by the FDA as an immune response modifier, but is limited to topical application due to its poor pharmacokinetics that causes undesired adverse effects. Nanoparticles are increasingly used with innate immune stimulators to mitigate side effects and enhance adjuvant efficacy. In this study, a potent small molecule TLR7 agonist, 2-methoxyethoxy-8-oxo-9-(4-carboxybenzyl)adenine (1V209), was conjugated to hollow silica nanoshells (NS). Pro-inflammatory cytokine (IL-6, IL-12) release by mouse bone marrow derived dendritic cells and human peripheral blood mononuclear cells revealed that the potency of silica nanoshells-TLR7 conjugates (NS-TLR) depends on nanoshell size and ligand coating density. Silica nanoshells of 100 nm diameter coated with a minimum of ~6,000 ...