Advanced pH-responsive copolymers for stabilizing lipid nanoparticles and manipulating their internal nanostructures

Abstract

Significant research effort has been directed towards non-lamellar lyotropic liquid crystalline lipid nanoparticles (LNPs), particularly cubosomes and hexosomes, due to their unique multidimensional porous structures and associated benefits including the capability of encapsulating hydrophilic, hydrophobic, and amphiphilic substances, high drug loading, and controlled drug release. In this study, novel amphiphilic block copolymers were synthesized using RAFT polymerization and used as stabilizers for cubosomes and hexosomes. These copolymers feature a hydrophilic polyethylene glycol (PEG) block, a hydrophobic hydrocarbon chain block, and a pH-responsive chemical group, specifically 2-(dimethylamino)ethyl methacrylate (DMAEMA) or diethylaminoethyl methacrylate (DEAEMA). The developed copolymers were then used to prepare monoolein (MO)- or phytantriol (PT)-based LNPs. Synchrotron small-angle X-ray scattering (SAXS) was utilized to identify their mesophase under various polymer concentrations and pH conditions. The results demonstrated that these novel copolymers could effectively stabilize LNPs, which also displayed composition- and pH-dependent internal mesophase structures. As the copolymer concentration and the length of the DMAEMA/DEAEMA segments increase, the membrane curvature also increases. These novel formulations are promising for controlled drug release for anticancer application. The pH-responsive behavior could reduce side effects on healthy cells and enhance therapeutic efficacy for cancer treatment.