학술논문
Proteasome Inhibitor-Loaded Micelles Enhance Antitumor Activity Through Macrophage Reprogramming by NF-κB Inhibition.
Document Type
Academic Journal
Author
Wu H; Innovation Center of NanoMedicine, Kawasaki Institute of Industrial Promotion, 3-25-14, Tonomachi, Kawasaki-ku, Kawasaki 210-0821, Japan.; Tao A; Department of Bioengineering, Graduate School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656, Japan.; Martin JD; Department of Bioengineering, Graduate School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656, Japan.; Quader S; Innovation Center of NanoMedicine, Kawasaki Institute of Industrial Promotion, 3-25-14, Tonomachi, Kawasaki-ku, Kawasaki 210-0821, Japan.; Liu X; Innovation Center of NanoMedicine, Kawasaki Institute of Industrial Promotion, 3-25-14, Tonomachi, Kawasaki-ku, Kawasaki 210-0821, Japan.; Takahashi K; Laboratory of Cancer Biology and Molecular Immunology, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.; Hespel L; Department of Bioengineering, Graduate School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656, Japan.; Miura Y; Department of Bioengineering, Graduate School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656, Japan.; Hayakawa Y; Laboratory of Cancer Biology and Molecular Immunology, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan; Division of Pathogenic Biochemistry, Department of Bioscience, Institute of Natural Medicine, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan.; Irimura T; Laboratory of Cancer Biology and Molecular Immunology, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan; Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan.; Cabral H; Department of Bioengineering, Graduate School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656, Japan. Electronic address: horacio@bmw.t.u-tokyo.ac.jp.; Kataoka K; Innovation Center of NanoMedicine, Kawasaki Institute of Industrial Promotion, 3-25-14, Tonomachi, Kawasaki-ku, Kawasaki 210-0821, Japan; Policy Alternatives Research Institute, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan. Electronic address: kataoka@bmw.t.u-tokyo.ac.jp.
Source
Publisher: Elsevier Country of Publication: United States NLM ID: 2985195R Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1520-6017 (Electronic) Linking ISSN: 00223549 NLM ISO Abbreviation: J Pharm Sci Subsets: MEDLINE
Subject
Language
English
Abstract
Macrophage reprogramming toward a tumor-attacking phenotype is a promising treatment strategy, yet such strategies are scarce and it is not clear how to combine them with cytotoxic therapies that are often used to treat solid tumors. Here, we evaluate whether a micelle-encapsulated proteasome inhibitor, that is, the peptide aldehyde drug MG132, which is cytotoxic to cancer cells, can reprogram macrophages to attack the tumor. Through in vitro studies, we demonstrated that the proteasome inhibition reduces nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling-a known promoter of tumor-supporting macrophages and chemoresistance-in both cancer cells and macrophages. In in vivo studies, we showed that, although free MG132 did not affect the macrophage phenotype in tumors even at its maximum tolerated dose, the micellar formulation of MG132 safely achieved simultaneous cancer cell killing and macrophage reprogramming, thereby enhancing the antitumor efficacy in a syngeneic, orthotopic breast cancer model.
(Copyright © 2017 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)
(Copyright © 2017 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)