Sensitizing Cancer Cells to TRAIL Mediated Cell Death by Mitoxantrone Loaded Theranostic Micelles

Abstract

TRAIL (Tumor necrosis factor-related Apoptosis Inducing Ligand) has been shown to induce death selectively in various cancer cells. However, several cancer cells are either resistant or can develop resistance to TRAIL-induced cell death. As a result, strategies that overcome this resistance are currently under investigation. We have recently discovered several FDA-approved drugs with TRAIL sensitization activity against prostate, breast and pancreatic cancer cells. Here we demonstrate successful encapsulation of a previously unknown TRAIL sensitizing chemotherapeutic drug, mitoxantrone, in PEG-DSPE micelles in order to facilitate delivery of the drug to cancer cells. Mitoxantrone was successfully encapsulated in three different PEG-DSPE micelles with methoxy, amine, and carboxyl termini, respectively. The different PEG-DSPE micelles were characterized for drug loading, size, zeta potential and cytotoxicity. The therapeutic efficacy of encapsulated mitoxantrone was investigated as a single agent treatment, as well as in combination with TRAIL in several cancer cell lines. The micelles were also conjugated with an MRI contrast agent in order to facilitate tumor imaging. Drug-loaded micelles were found to maintain mitoxantrone’s sensitization activity in both single agent and sequential drug-protein treatments in inducing synergistic apoptotic activity. Our results suggest that micelle-encapsulated mitoxantrone can be employed simultaneously for synergistic treatments and imaging applications in cancer diseases.

Keywords: TRAIL, PEG-DSPE, micelles, mitoxantrone, FDA, cancer.