Novel tumor-targeted liposomes comprised of an MDM2 antagonist plus proteasome inhibitor display anti-tumor activity in a xenograft model of bortezomib-resistant Waldenstrom macroglobulinemia

Abstract

Targeted drug delivery remains an active area of investigation in hematologic cancers. We have previously reported on a novel nanoparticle formulation (D1X) that can encapsulate drugs within a liposome whose lipid bilayer contains dexamethasone, which serves as a targeting ligand for drug delivery to tumor cells that express glucocorticoid receptors. We tested the activity of D1X-encapsulated bortezomib (D1XB) in combination with D1X-encapsulated nutlin (D1XN) in B-lymphoma/Waldenstrom macroglobulinemia (WM) cells. WM cells treated with D1XB + D1XN experienced cell cycle arrest, ER stress and apoptosis. In mice xenografted with bortezomib-resistant WM cells, D1XB + D1XN treatment resulted in significantly lower tumor burden compared to vehicle or nonliposomal parent drugs. In vivo biodistribution studies showed minimal uptake of D1X-based drugs in normal mice tissues. Our studies demonstrate that highly targeted delivery of both bortezomib and nutlin encapsulated in D1X nanoparticles are cytotoxic to and delay in vivo growth of bortezomib-resistant WM cells.