1. Tumor microenvironment-targeted nanoparticles loaded with bortezomib and ROCK inhibitor improve efficacy in multiple myeloma.
- Author
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Federico C, Alhallak K, Sun J, Duncan K, Azab F, Sudlow GP, de la Puente P, Muz B, Kapoor V, Zhang L, Yuan F, Markovic M, Kotsybar J, Wasden K, Guenthner N, Gurley S, King J, Kohnen D, Salama NN, Thotala D, Hallahan DE, Vij R, DiPersio JF, Achilefu S, and Azab AK
- Subjects
- Amides pharmacology, Amides therapeutic use, Animals, Apoptosis drug effects, Bortezomib pharmacology, Cell Adhesion drug effects, Cell Line, Tumor, Cell Movement drug effects, Cell Proliferation drug effects, Cell Survival drug effects, Disease Progression, Focal Adhesion Protein-Tyrosine Kinases metabolism, Human Umbilical Vein Endothelial Cells drug effects, Human Umbilical Vein Endothelial Cells metabolism, Humans, Liposomes, Membrane Glycoproteins metabolism, Mice, P-Selectin metabolism, Protein Binding, Protein Kinase Inhibitors pharmacology, Pyridines pharmacology, Pyridines therapeutic use, Signal Transduction drug effects, Tumor Burden, rho-Associated Kinases metabolism, src-Family Kinases metabolism, Bortezomib therapeutic use, Multiple Myeloma drug therapy, Multiple Myeloma pathology, Nanoparticles chemistry, Protein Kinase Inhibitors therapeutic use, Tumor Microenvironment drug effects, rho-Associated Kinases antagonists & inhibitors
- 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.
- Published
- 2020
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