Combination Anticancer Nanopreparations of Novel Proapoptotic Drugs and TRAIL Ligand

Abstract

Cancer cells are known to use multiple pathways and mechanisms to promote survival and proliferation. In addition, some tumors are able to acquire resistance to various drugs over the course of treatment. As such, combination therapies targeting different dysregulated pathways have emerged as a powerful approach to treat cancer and multidrug resistant (MDR) tumors. PEG-PE micelles have been used to increase the solubility of a variety of poorly soluble drugs. In addition to advantages of increased solublization and stability, the surface of these nanoparticles can be decorated with a variety of moieties to create multifunctional delivery vehicles. This project aims to deliver novel pro-apoptotic drugs targeting the PI3-kinase pathway, in PEG-PE micelles surface modified with TNF-related Apoptosis Inducing Ligand (TRAIL) as a combined nanoformulation. These poorly soluble drugs are effectively loaded into PEG-PE micelles (~70% loading efficiency). TRAIL is efficiently conjugated (~85%) to the surface of micelles by reaction with pNP-PEG-PE included in the micelle preparation. Combined preparations of drug-loaded and TRAIL-modified micelles were shown to have a synergistic effect against a variety of cell lines including A2780, U87-MG, DU-145 and the Taxol resistant SKOV-3 TR when compared to individual treatments. These results indicate the potential benefits of micellar proapoptotic drug combined with surface modified with TRAIL.