Stimulation of toll-like receptor (TLR)7/8 activity in dendritic cells is known to promote pro-inflammatory cytokine secretion and co-stimulatory molecule upregulation. However, currently available TLR7 and 7/8 agonists exhibit unfavorable pharmacokinetics, limiting their <i>in vivo</i> efficacy. To enable efficient delivery to antigen presenting cells, we encapsulated a novel imidazoquinoline-based TLR7/8 agonist in pH responsive polymeric nanoparticles. Enhanced co-stimulatory molecule expression on dendritic cells, stronger pro-inflammatory cytokine response and improved antigen-presentation via MHC I was observed with NP-encapsulated agonist compared to that with the soluble form. In vivo studies showed that the pH-responsive formulation elicited stronger antigen-specific CD8 T cell and natural killer (NK) cell responses, resulting in enhanced anticancer efficacy in murine melanoma model. In addition, TLR7/8 agonist-loaded NPs potentiated in vitro antibody-dependent cell cytotoxicity (ADCC) mediated by the epidermal growth factor receptor targeting antibody cetuximab. TLR7/8 agonist-loaded NP treatment significantly enhanced the anti-tumor efficacy of cetuximab and an anti-HER2/neu antibody in mouse tumor models. Our results suggest that acidic-pH responsive polymeric nanoparticles are an efficient TLR7/8 agonist delivery platform for cancer immunotherapy.

Nanoparticle encapsulated TLR7/8 agonists activate both innate and adaptive immune responses

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.