pH-sensitive amphiphilic copolymer brush Chol-g-P(HEMA-co-DEAEMA)-b-PPEGMA: synthesis and self-assembled micelles for controlled anti-cancer drug release

Abstract

Typical cholesterol modified amphiphilic copolymers poly((hydroxyethyl methylacrylate)-co-(2-(diethylamino)ethyl methacrylate))-b-poly(poly(ethylene glycol) methyl ether methacrylate) (Chol-g-P(HEMA-co-DEAEMA)-b-PPEGMA) with specific pH-sensitive/hydrophilic/hydrophobic structures containing different ratios of pH-sensitive PDEAEMA segments were designed and synthesized via the combination of activators regenerated by electron transfer atom transfer radical polymerization (ARGET ATRP) and alcoholysis reaction, and their self-assembled three-layered micelles were used as doxorubicin (DOX) delivery carriers. The structures of the polymers were determined by ¹H NMR and GPC. The critical micelle concentrations (CMC) of the polymers at different pH values were confirmed by fluorescence spectroscopy, resulting in 9.33 mg L⁻¹ and 13.18 mg L⁻¹ for two polymers even at weakly acidic conditions (pH 6.0). The pK_b values, particle sizes and zeta potentials of the polymers in the solutions with different pH values were studied in order to investigate the pH-sensitivity of the polymers. The morphological shapes of the polymers were detected by transmission electron microscopy (TEM). As the pH decreased, the sizes and zeta potentials of the polymeric micelles increased markedly. DOX was loaded in the micelles by the dialysis method, and the in vitro release rate was enhanced sharply with the solution pH of 6.0 when compared to pH of 7.4 for both of the polymers. The cytotoxic effects for HepG2 cells were measured and compared with free DOX, resulting in low and high cytotoxicity for polymers and DOX-loaded micelles, respectively. All the results demonstrated that these pH-sensitive micelles could be used as the potential anti-cancer drug carriers.