Dual-Layer Surface Coating of PLGA-Based Nanoparticles Provides Slow-Release Drug Delivery To Achieve Metronomic Therapy in a Paclitaxel-Resistant Murine Ovarian Cancer Model

Development of drug resistance is a central challenge to the treatment of ovarian cancer. Metronomic chemotherapy decreases the extent of drug-free periods, thereby hindering development of drug resistance. Intraperitoneal chemotherapy allows for treatment of tumors confined within the peritoneum, but achieving sustained tumor-localized chemotherapy remains difficult. We hypothesized that modulating the surface properties of poly­(lactic-<i>co</i>-glycolic acid) (PLGA)-based nanoparticles could enhance their drug retention ability and extend their release profile, thereby enabling metronomic, localized chemotherapy <i>in vivo</i>. Paclitaxel was encapsulated in particles coated with a layer of polydopamine and a subsequent layer of poly­(ethylene glycol) (PEG). These particles achieved a 3.8-fold higher loading content compared to that of nanoparticles formulated from linear PLGA–PEG copolymers. <i>In vitro</i> release kinetic studies and <i>in vivo</i> drug distribution profiles demonstrate sustained release of paclitaxel. Although free drug conferred no survival advantage, low-dose intraperitoneal administration of paclitaxel-laden surface-coated nanoparticles to drug-resistant ovarian tumor-bearing mice resulted in significant survival benefits in the absence of any apparent systemic toxicity