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.

Keywords:

• Waldenstrom macroglobulinemia
• bortezomib
• nanoparticles

Acknowledgments

We thank NanoDev Therapeutics for providing D1 lipid. We thank Dr. Laura Lewis-Tuffin for her scientific and technical support on cell cycle and apoptotis experiments, which were performed using an Attune NxT flow cytometer (Invitrogen) in the Mayo Florida Cellular Imaging and Flow Cytometry Shared Resource. The authors thank CSIR-IICT for collaboration. This is IICT communication number: IICT/Pubs./2019/357

Disclosure statement

Asher Chanan-Khan and Debarata Mukhopadhyay hold stock in NanoDev Therapeutics.

Author contributions

V.S.M and A.P. designed and performed the research, analyzed and interpreted the data, wrote the manuscript, and approved the final draft. S.A. performed the research, analyzed the data and approved the final draft. A.M performed the research, analyzed the data and approved the final draft. H.R.R maintained animal colonies, performed the research and approved the final draft. R.B. provided reagents for research, provided critical scientific oversight and approved the final draft. D.M. designed the research, analyzed the data, provided critical scientific and intellectual oversight, wrote the manuscript, and approved the final draft. A.A.C-K. designed the research, analyzed the data, provided critical scientific and intellectual oversight, wrote the manuscript, and approved the final draft.

Additional information

Funding

NIH grants CA150190 and CA78383 supported this work, Florida Department of Health Cancer Research Chair Fund awarded (#3 J) to D.M. The experiments and analysis carried out in this study were supported in part by the Daniel Foundation of Alabama (AC-K), the Predolin Foundation (AC-K) and the Mayo Clinic Cancer Center (CA015083, AC-K).