Toward understanding polymeric micelle stability regulated by diverse physico-chemical strategies and their stabilized mechanism

Despite polymeric micelles as a kind of promising drug delivery system (DDS), their unsatisfactory stability in physiological environment remains a barrier to clinical translation. Thus, the present study aims at understanding the factors and underlying mechanism to stabilize micelles. Accordingly, we designed triblock copolymers poly(2-phenoxyethyl methacrylate)-b-poly(2-oxopropyl methacrylate)-b-poly[poly(ethylene glycol) methyl ether methacrylate] (PPOEMA-b-POPMA-b-PPEGMA), and prepared cross-linked polymeric micelles (CPM) self-assembled by these copolymers. Förster resonance energy transfer (FRET) fluorescence test showed cross-linked structure was more stable in diluted environment. Meanwhile, cross-linking and higher proportion of hydrophilic shell retarded the dissociation of micelles after incubating with protein. Experiment and simulation results revealed stabilized mechanism of micelles regulated by different strategies. Firstly, Van der Waals interaction between benzene rings would be the driving force of micelle stability. Secondly, cross-linking reshaped micelle structure, thereby evoking π-π stacking effect and simultaneously limiting movement of polymer segments, resulting in the more rigid micelle structure. Then, longer hydrophilic branch chain led to better coverage of hydrophilic shell, conducive to micelle stability in thermodynamics. In addition, doxorubicin (DOX)-loaded micelles possessed pH-responsive property and remarkably inhibited the growth of tumor cells. These findings are of significance in further understanding of polymeric micelle stability, and provide new insight for the design of stable and long-circulating materials for drug delivery.