Nanomedicines Eradicating Cancer Stem-like Cells in Vivo by pH-Triggered Intracellular Cooperative Action of Loaded Drugs.
Nanomedicines capable of control over drug functions have potential for developing resilient therapies, even against tumors harboring recalcitrant cancer stem cells (CSCs). By coordinating drug interactions within the confined inner compartment of core-shell nanomedicines, we conceived multicomponent nanomedicines directed to achieve synchronized and synergistic drug cooperation within tumor cells as a strategy for enhancing efficacy, overcoming drug resistance, and eradicating CSCs. The approach was validated by using polymeric micellar nanomedicines co-incorporating the pan-kinase inhibitor staurosporine (STS), which was identified as the most potent CSC inhibitor from a panel of signaling-pathway inhibitors, and the cytotoxic agent epirubicin (Epi), through rationally contriving the affinity between the drugs. The micelles released both drugs simultaneously, triggered by acidic endosomal pH, attaining concurrent intracellular delivery, with STS working as a companion for Epi, down-regulating efflux transporters and resistance mechanisms induced by Epi. These features prompted the nanomedicines to eradicate orthotopic xenografts of Epi-resistant mesothelioma bearing a CSC subpopulation.
Innovation Center of NanoMedicine , 3-25-14 Tonomachi, Kawasaki-ku, Kawasaki 210-0821, Japan.
Hiroaki
H
Kinoh
Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo , 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
Yutaka
Y
Miura
Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo , 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
Tsukasa
T
Chida
Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo , 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
Xueying
X
Liu
Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo , 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
Kazue
K
Mizuno
Department of Materials Engineering, Graduate School of Engineering, The University of Tokyo , 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656, Japan.
Shigeto
S
Fukushima
Department of Innovative Applied Oncology, Graduate School of Medical Sciences, Kyushu University , 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.
Yosuke
Y
Morodomi
Polymer Chemistry Division, Chemical Resources Laboratory, Tokyo Institute of Technology , R1-11, 4259 Nagatsuta, Midori-ku, Yokohama 226-8503, Japan.
Nobuhiro
N
Nishiyama
Department of Bioengineering, Graduate School of Engineering, The University of Tokyo , 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656, Japan.
Horacio
H
Cabral
Innovation Center of NanoMedicine , 3-25-14 Tonomachi, Kawasaki-ku, Kawasaki 210-0821, Japan.|Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo , 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.|Department of Materials Engineering, Graduate School of Engineering, The University of Tokyo , 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656, Japan.|Department of Bioengineering, Graduate School of Engineering, The University of Tokyo , 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656, Japan.
Kazunori
K
Kataoka
D000970:Antineoplastic Agents / Q000008:administration & dosage*; D045744:Cell Line, Tumor; D015251:Epirubicin / Q000008:administration & dosage; D006801:Humans; D008823:Micelles; D050997:Nanomedicine; D014411:Neoplastic Stem Cells
D000970:Antineoplastic Agents; D008823:Micelles; D015251:Epirubicin
cancer stem-like cells; chemotherapy; epirubicin; mesothelioma; polymeric micelles; staurosporine