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

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

Authors :
Katherine Wasden
Pilar de la Puente
Barbara Muz
Ravi Vij
Samuel Achilefu
Dinesh Thotala
Justin King
Daniel Kohnen
Dennis E. Hallahan
Feda Azab
Fangzheng Yuan
Cinzia Federico
Matea Markovic
Kathleen Duncan
Luna Zhang
Jennifer Sun
John F. DiPersio
Abdel Kareem Azab
Joseph Kotsybar
Vaishali Kapoor
Gail Sudlow
Nicole Guenthner
Kinan Alhallak
Noha N. Salama
Shannon Gurley
Source :
Nature Communications, Nature Communications, Vol 11, Iss 1, Pp 1-13 (2020)
Publication Year :
2020
Publisher :
Springer Science and Business Media LLC, 2020.

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.<br />The tumour microenvironment (TME) has a major role in chemoresistance in multiple myeloma. The authors show that a nanoparticle targeted to TME and loaded with bortezomib (BTZ) and Y27632 is more effective than free drugs, non-targeted and single-agent controls and reduces BTZ-related side effects.

Details

ISSN :
20411723
Volume :
11
Database :
OpenAIRE
Journal :
Nature Communications
Accession number :
edsair.doi.dedup.....e14060bd7bccf7eab65002ce7a781919
Full Text :
https://doi.org/10.1038/s41467-020-19932-1