469000 In Situ crosslinked Endosomolytic Polymeric Vesicles for Immunotherapeutic Targeting of the Sting Pathway
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.
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