(596e) In Situ crosslinked Endosomolytic Polymeric Vesicles for Immunotherapeutic Targeting of the Sting Pathway

Cyclic dinucleotides (CDNs) are an emerging class of immunomodulators that have shown particular promise in cancer immunotherapy for their ability to elicit the production of type I interferons and trigger the generation antitumor leukocyte phenotypes in immunosuppressive tumor microenvironments (TMEs). The endogenous ligand of the stimulator interferon genes (STING), 2â??3â?? cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) has recently shown promise as an immunotherapeutic capable of eliciting tumor regression and immune memory. However, a number of drug delivery barriers limit the therapeutic efficacy and translation of CDNs, including nuclease degradation, poor intracellular uptake, and inefficient cytosolic delivery. To address this challenge, we have developed polymeric vesicles that actively enhance endosomal escape of cyclic dinucleotides for efficient delivery to the cytosolic STING receptor.

Reversible addition-fragmentation chain transfer (RAFT) polymerization was used to synthesize poly[(ethylene glycol)-b-(butyl methacrylate-co-diethylamino ethyl methacrylate-co-pyridyl disulfide ethyl methacrylate)] (PEG-b-DBP) amphiphilic diblock polymers that self-assemble into endosomolytic pH-responsive vesicles with d < 100 nm in aqueous conditions with neutral surface charge. Vesicles encapsulated cGAMP with efficiencies of 38% and significantly enhanced potency in vitro, manifesting in multiple order of magnitude decreases in cGAMP EC50 when encapsulated. Nanoparticle cGAMP formulations demonstrated significant inhibition of tumor growth and increased mouse survival times in a murine melanoma model. Collectively, these data demonstrate that endosomolytic polymer nanoparticles significantly improve CDN potency by enhancing delivery to the cytosolic STING sensor and suggest that encapsulated cGAMP formulations may prove to be a powerful cancer immunotherapeutic.