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Tytuł:
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Tumor microenvironment-targeted nanoparticles loaded with bortezomib and ROCK inhibitor improve efficacy in multiple myeloma.
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Autorzy:
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Federico C; Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO, USA.
Alhallak K; Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO, USA.; Department of Biomedical Engineering, Washington University, St. Louis, MO, USA.
Sun J; Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO, USA.; Department of Biomedical Engineering, Washington University, St. Louis, MO, USA.
Duncan K; Department of Radiology, Washington University School of Medicine, St. Louis, MO, USA.
Azab F; Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO, USA.
Sudlow GP; Department of Radiology, Washington University School of Medicine, St. Louis, MO, USA.
de la Puente P; Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO, USA.
Muz B; Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO, USA.
Kapoor V; Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO, USA.
Zhang L; Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO, USA.; Department of Biomedical Engineering, Washington University, St. Louis, MO, USA.
Yuan F; Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO, USA.; Department of Pharmaceutical and Administrative Sciences, St. Louis College of Pharmacy, St. Louis, MO, USA.
Markovic M; Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO, USA.; Department of Pharmaceutical and Administrative Sciences, St. Louis College of Pharmacy, St. Louis, MO, USA.
Kotsybar J; Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO, USA.; Department of Pharmaceutical and Administrative Sciences, St. Louis College of Pharmacy, St. Louis, MO, USA.
Wasden K; Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO, USA.
Guenthner N; Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO, USA.
Gurley S; Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO, USA.
King J; Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA.
Kohnen D; Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA.
Salama NN; Department of Pharmaceutical and Administrative Sciences, St. Louis College of Pharmacy, St. Louis, MO, USA.; Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Cairo University, Cairo, Egypt.
Thotala D; Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO, USA.
Hallahan DE; Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO, USA.
Vij R; Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA.
DiPersio JF; Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA.
Achilefu S; Department of Biomedical Engineering, Washington University, St. Louis, MO, USA.; Department of Radiology, Washington University School of Medicine, St. Louis, MO, USA.
Azab AK; Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO, USA. .; Department of Biomedical Engineering, Washington University, St. Louis, MO, USA. .
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Źródło:
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Nature communications [Nat Commun] 2020 Nov 27; Vol. 11 (1), pp. 6037. Date of Electronic Publication: 2020 Nov 27.
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Typ publikacji:
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Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't
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Język:
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English
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Imprint Name(s):
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Original Publication: [London] : Nature Pub. Group
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MeSH Terms:
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Tumor Microenvironment*/drug effects
Bortezomib/*therapeutic use
Multiple Myeloma/*drug therapy
Multiple Myeloma/*pathology
Nanoparticles/*chemistry
Protein Kinase Inhibitors/*therapeutic use
rho-Associated Kinases/*antagonists & inhibitors
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
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References:
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Grant Information:
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TL1 TR002344 United States TR NCATS NIH HHS; P30 AR074992 United States AR NIAMS NIH HHS; U54 CA199092 United States CA NCI NIH HHS; P30 CA091842 United States CA NCI NIH HHS; UL1 TR002345 United States TR NCATS NIH HHS
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Substance Nomenclature:
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0 (Amides)
0 (Liposomes)
0 (Membrane Glycoproteins)
0 (P-Selectin)
0 (P-selectin ligand protein)
0 (Protein Kinase Inhibitors)
0 (Pyridines)
138381-45-0 (Y 27632)
69G8BD63PP (Bortezomib)
EC 2.7.10.2 (Focal Adhesion Protein-Tyrosine Kinases)
EC 2.7.10.2 (src-Family Kinases)
EC 2.7.11.1 (rho-Associated Kinases)
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Entry Date(s):
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Date Created: 20201128 Date Completed: 20201210 Latest Revision: 20221130
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Update Code:
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20240105
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PubMed Central ID:
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PMC7699624
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DOI:
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10.1038/s41467-020-19932-1
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PMID:
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33247158
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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.
