Nanomicelles, by virtue of their prominent biocompatibility, degradability, and ability to solubilize hydrophobic drugs, have been widely used as the most effective delivery platform for anticancer drugs. However, undesirable drug-loading capacity, unfeasible modification, poor in vivo stability, and intratumoral penetration remain to be addressed. Herein, we introduce a novel core/shell PEGylated poly(glycerol sebacate) (PEGS)/hydroxyapatite (HA) hybrid nanomicelle based on a unique triblock PEGS substrate with functional carboxyls in terminals and free hydroxyls as pendant groups. The hydrophobic doxorubicin (DOX) can be controllably encapsulated in the core of nanomicelles via hydrogen bonding, and ensuing in situ mineralization of HA occurs as a shell layer with the electrostatic effect between the carboxylate radical (COO-) and calcium ion (Ca2+). Through optimizing the coordination of PEGS nanomicelles and HA mineralization, 20-30 nm spherical nanoparticles can be formed with considerable drug loading (0.38 mg DOX/1 mg nanoparticles) and a sensitive pH-responsive release (about 50% release amount at pH 5.6 while <5% release amount at pH 7.4 in 24 h). In further in vitro studies, this PEGS/HA hybrid nanoparticle system exhibits excellent selective tumor inhibitory efficacy, while in in vivo studies, high efficacy of tumor suppression and low incidence of toxicity can be evidenced in a DOX-loaded PEGS/HA group (71.7% decrease in average tumor volume compared to a control group after 15 day hypodermic treatment). The core/shell PEGS/HA nanoparticle coordinated with PEGS nanomicelles and in situ HA mineralization represents high drug-loading capacity, multifunctional possibility, and tumor-selective and responsive release profiles and could offer a highly promising platform for tumor therapy in clinical application.
Keywords: PEGylated poly(glycerol sebacate) (PEGS); anticancer therapy; hydroxyapatite (HA); multifunctionality; nanomicelle.