Exploring the Phase Behavior of Peg-Grafted Polyelectrolytes for Intracellular Drug Delivery

The cellular and endosomal membranes represent a significant delivery barrier in the administration of therapeutics whose targets lie in the cytosol. To address this challenge, several investigators have developed cationic and pH responsive self-assembling polymers to facilitate the uptake and endosomal escape of cargo into the cytosol. To date, these approaches have largely leveraged cationic and pH responsive homopolymers or block copolymers, and as such design rules for other polymer architectures for maximizing the delivery efficiency of therapeutics to the cytosol have been poorly explored. Here we synthesize a library of poly[(poly(ethylene glycol) methyl ether methacrylate)-co-(butyl methacrylate)-co-(2-(diethylanimo)ethyl methacrylate)] (PEGMA-c-DB) graft copolymers for evaluation as mediators of cytosolic delivery. Polymers are synthesized via one pot RAFT polymerization, and PEG graft length, total chain molecular weight, and PEGMA weight percent are systematically and combinatorically varied to determine the effects of these changes on the self-assembled polymer architecture in aqueous media. By evaluating self-assembled particle yields, hydrodynamic radii, and with TEM analysis, we demonstrate that similar to in block copolymer architectures, large weight percents of PEGMA typically yield micellar self-assembled nanoparticulates, while smaller PEGMA weight percents typically yield wormlike and vesicular structures. However, unlike linear architectures, our PEGMA-c-DB system was capable of supporting vesicular self-assembly at molecular weights as large as M_w = 25,000, which we also demonstrate to be desirable for facilitating efficient endosomal escape. Collectively, these data demonstrate that PEGMA-c-DB polymers are useful formulation of endosomolytic vesicles, which are promising candidates for versatile cytosolic delivery of cargos.