The generation of robust T cell responses against tumor antigen requires antigen to be delivered to antigen presenting cells in lymphoid tissue in combination with innate activation stimuli. Here, we report on the design of lipid nanoparticles that allow for efficient lymphatic drainage in combination with co-delivery of peptide antigen and small molecule TLR agonists. Poly-L-glutamic acid (PGA) served as a scaffold for conjugation or either imidazoquinoline TLR7/8 agonist (TLRa) or peptide antigen. PGA-TLRa and PGA-peptide were subsequently formulated by electrostatic interaction into lipid nanoparticles using ionizable lipids and PEGylated lipids to provide colloidal stabilization. Field flow fractionation in combination with fluorescence and light scattering detection showed that lipid nanoparticles with a mean size of 60 nm were obtained with an encapsulation efficiency of PGA to be above 99 %. In vitro cell uptake and toxicity measurements strongly correlated with the pKa of the ionizable lipids, showing that ionizable lipids with a pKa below physiological pH were non-toxic while still allowing for cellular uptake. Also in vitro antigen and TLR agonist loaded nanoparticles were able to induce both innate immune activation and antigen presentation. In vivo experiments in mice showed strong accumulation of nanoparticles in draining lymphoid tissue and induction of localized innate immune activation in lymph nodes and in the spleen. Furthermore, we demonstrate that lipid nanoparticles can mount T cell responses against encapsulated peptide antigen. These findings strongly suggest that this nanoparticle design holds potential for the development of cancer vaccines. <br/>

Lymphoid targeting of peptide antigen and TLR agonists by lipid nanoparticles

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.