title: Eradication of CD44-variant positive population in head and neck tumors through controlled intracellular navigation of cisplatin-loaded nanomedicines.
abstract: Eventual relapse of tumor growth is commonly observed in head and neck cancer patients, following treatment with platinum-based chemotherapies. This occurrence is believed to be related to the failure to eradicate drug resistant, cancer stem cell (CSC) niches, thereby enriching their population in tumors after treatment. In this study, we show that in contrast to free cisplatin (CDDP), the polymer micelle-based nanomedicine incorporating cisplatin (CDDP/m), can eradicate both the undifferentiated cell and the differentiated cancer cell populations within a head and neck tumor model. Immunohistochemistry of treated tumors showed that opposing to CDDP treatment, CDDP/m could reduce tumor growth without concentrating the CSC-like population. We further showed that CDDP/m, but not CDDP, can localize into hypoxic regions, possibly CSC-rich areas, in the tumors, and can overcome their detoxification mechanism based-on high cellular expression of glutathione to successfully deliver Pt to nuclear DNA. Our data suggests CDDP/m to be a replacement for current platinum therapies, for its ability to eradicate both bulk and CSC-like populations, and in turn to prevent recurrence of tumor growth.
authors.affiliation: Department of Materials Engineering, Graduate School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8654, Japan.
authors.forename: Ming
authors.initials: M
authors.lastname: Wang
authors.affiliation: Division of Clinical Biotechnology, 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.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Miura
authors.affiliation: Division of Gene Regulation, Institute for Advanced Medical Research, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan; Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, 3-1-1, Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Tsuchihashi
authors.affiliation: Division of Clinical Biotechnology, 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.
authors.forename: Kazuki
authors.initials: K
authors.lastname: Miyano
authors.affiliation: Division of Gene Regulation, Institute for Advanced Medical Research, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Nagano
authors.affiliation: Division of Gene Regulation, Institute for Advanced Medical Research, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
authors.forename: Momoko
authors.initials: M
authors.lastname: Yoshikawa
authors.affiliation: Division of Clinical Biotechnology, 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.
authors.forename: Ami
authors.initials: A
authors.lastname: Tanabe
authors.affiliation: Division of Clinical Biotechnology, 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.
authors.forename: Jun
authors.initials: J
authors.lastname: Makino
authors.affiliation: Innovation Center of Nanomedicine, Kawasaki Institute of Industry Promotion, 66-20 Horikawa-cho, Saiwai-ku, Kawasaki 212-0013, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Mochida
authors.affiliation: Innovation Center of Nanomedicine, Kawasaki Institute of Industry Promotion, 66-20 Horikawa-cho, Saiwai-ku, Kawasaki 212-0013, Japan; Polymer Chemistry Division, Chemical Resources Laboratory, Tokyo Institute of Technology, R1-11, 4259 Nagatsuta, Midori-ku, Yokohama 226-8503, Japan.
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Nishiyama
authors.affiliation: Division of Gene Regulation, Institute for Advanced Medical Research, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Saya
authors.affiliation: 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.
authors.forename: Horacio
authors.initials: H
authors.lastname: Cabral
authors.affiliation: Department of Materials Engineering, Graduate School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8654, Japan; Division of Clinical Biotechnology, 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; Innovation Center of Nanomedicine, Kawasaki Institute of Industry Promotion, 66-20 Horikawa-cho, Saiwai-ku, Kawasaki 212-0013, Japan; Department of Bioengineering, Graduate School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656, Japan; Center for Disease Biology and Integrative Medicine, Graduate School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656, Japan. Electronic address: kataoka@bmw.t.u-tokyo.ac.jp.
authors.forename: Kazunori
authors.initials: K
authors.lastname: Kataoka
mesh_terms: D000444:Aldehyde Dehydrogenase / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000494:pharmacology / Q000627:therapeutic use; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000008:administration & dosage* / Q000494:pharmacology / Q000627:therapeutic use; D004247:DNA / Q000378:metabolism; D004337:Drug Carriers / Q000008:administration & dosage* / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism*; D008807:Mice, Inbred BALB C; D008823:Micelles; D050997:Nanomedicine; D010984:Platinum / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; C497483:CD44 protein, human; D004337:Drug Carriers; D018960:Hyaluronan Receptors; D008823:Micelles; D010984:Platinum; D004247:DNA; D000444:Aldehyde Dehydrogenase; D002945:Cisplatin
keywords: CD44-variant; Cancer therapy; Drug delivery; Head and neck tumor; Polymeric micelle