Tumor microenvironment-targeted nanoparticles loaded with bortezomib and ROCK inhibitor improve efficacy in multiple myeloma

Cinzia Federico, Kinan Alhallak, Jennifer Sun, Kathleen Duncan, Feda Azab, Gail P. Sudlow, Pilar de la Puente, Barbara Muz, Vaishali Kapoor, Luna Zhang, Fangzheng Yuan, Matea Markovic, Joseph Kotsybar, Katherine Wasden, Nicole Guenthner, Shannon Gurley, Justin King, Daniel Kohnen, Noha N. Salama, Dinesh ThotalaDennis E. Hallahan, Ravi Vij, John F. DiPersio, Samuel Achilefu, Abdel Kareem Azab

Research output: Contribution to journalArticlepeer-review

18 Scopus citations

Abstract

Drug resistance and dose-limiting toxicities are significant barriers for treatment of multiple myeloma (MM). Bone marrow microenvironment (BMME) plays a major role in drug resistance in MM. Drug delivery with targeted nanoparticles have been shown to improve specificity and efficacy and reduce toxicity. We aim to improve treatments for MM by (1) using nanoparticle delivery to enhance efficacy and reduce toxicity; (2) targeting the tumor-associated endothelium for specific delivery of the cargo to the tumor area, and (3) synchronizing the delivery of chemotherapy (bortezomib; BTZ) and BMME-disrupting agents (ROCK inhibitor) to overcome BMME-induced drug resistance. We find that targeting the BMME with P-selectin glycoprotein ligand-1 (PSGL-1)-targeted BTZ and ROCK inhibitor-loaded liposomes is more effective than free drugs, non-targeted liposomes, and single-agent controls and reduces severe BTZ-associated side effects. These results support the use of PSGL-1-targeted multi-drug and even non-targeted liposomal BTZ formulations for the enhancement of patient outcome in MM.

Original languageEnglish
Article number6037
JournalNature communications
Volume11
Issue number1
DOIs
StatePublished - Dec 2020

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