Products Cited in Publications Worldwide Environment-Sensitive Polymeric Micelles Encapsulating SN-38 Potently Suppress Growth of Neuroblastoma Cells Exhibiting Intrinsic and Acquired Drug Resistance

Environment-Sensitive Polymeric Micelles Encapsulating SN-38 Potently Suppress Growth of Neuroblastoma Cells Exhibiting Intrinsic and Acquired Drug Resistance

Polunin, Yehor; Alferiev, Ivan S.; Brodeur, Garrett M.; Voronov, Andriy; Chorny, Michael

DOI: PMID:

Abstract

Conventional treatment approaches fail to provide durable control over aggressive malignancies due to intrinsic or acquired drug resistance characteristic of high-risk disease. SN-38, a potent camptothecin analog specifically targeting DNA topoisomerase I cleavage complexes, has shown promise in preclin. studies against aggressive solid tumors. However, its clin. utility is limited by inadequate solubility in pharmaceutically acceptable vehicles and by poor chem. and metabolic stability. Micelles formulated from amphiphilic invertible polymers (AIPs) can address these issues by concomitantly enabling solubilization of water-insoluble mol. cargoes and by protecting chem. labile agents from inactivation. Furthermore, the inversion of the AIP and disruption of the carrier-drug complexes triggered by contact with cell membranes makes it possible to deliver the therapeutic payload into the cell interior without compromising its biol. activity. In the present study, we characterized a novel AIP-based micellar formulation of SN-38 and evaluated its growth inhibitory effect on neuroblastoma (NB) cells derived either at diagnosis or at relapse after intensive chemoradiotherapy. Colloidally stable, drug-loaded micellar assemblies with a uniform <100 nm size were prepared using an AIP consisting of alternating blocks of poly(ethylene glycol) and polytetrahydrofuran (PEG600-PTHF650). The micellar drug applied in a low nanomolar range (10-50 nM) completely suppressed the growth of chemo-naïve NB cells even after a brief (10 min) exposure. Furthermore, extending the exposure to 24 h resulted in a profound and lasting inhibitory effect of the micellar formulation on the growth of NB cells exhibiting an acquired loss of p53 function. These results suggest that micelle-mediated delivery of SN-38 can potentially offer a new and effective strategy for treating different phases of high-risk disease, including those showing poor response to conventional therapies.

Keywords

invertible polymer micelles ; amphiphilic invertible polymers ; camptothecin ; SN-38 ; high-risk neuroblastoma ; drug resistance ; solid tumor