title: Enhanced efficacy against cervical carcinomas through polymeric micelles physically incorporating the proteasome inhibitor MG132.
abstract: Treatment of recurrent or advanced cervical cancer is still limited, and new therapeutic choices are needed for improving prognosis and quality of life of patients. Because human papilloma virus (HPV) infection is critical in cervical carcinogenesis, with the E6 and E7 oncogenes of HPV degrading tumor suppressor proteins through the ubiquitin proteasome system, the inhibition of the ubiquitin proteasome system appears to be an ideal target to suppress the growth of cervical tumors. Herein, we focused on the ubiquitin proteasome inhibitor MG132 (carbobenzoxy-Leu-Leu-leucinal) as an anticancer agent against cervical cancer cells, and physically incorporated it into micellar nanomedicines for achieving selective delivery to solid tumors and improving its in vivo efficacy. These MG132-loaded polymeric micelles (MG132/m) showed strong tumor inhibitory in vivo effect against HPV-positive tumors from HeLa and CaSki cells, and even in HPV-negative tumors from C33A cells. Repeated injection of MG132/m showed no significant toxicity to mice under analysis by weight change or histopathology. Moreover, the tumors treated with MG132/m showed higher levels of tumor suppressing proteins, hScrib and p53, as well as apoptotic degree, than tumors treated with free MG132. This enhanced efficacy of MG132/m was attributed to their prolonged circulation in the bloodstream, which allowed their gradual extravasation and penetration within the tumor tissue, as determined by intravital microscopy. These results support the use of MG132 incorporated into polymeric micelles as a safe and effective therapeutic strategy against cervical tumors.
authors.affiliation: Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Matsumoto
authors.affiliation: Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Miyamoto
authors.affiliation: Department of Bioengineering, Graduate School of Engineering, The University of Tokyo, Tokyo, Japan.
authors.forename: Horacio
authors.initials: H
authors.lastname: Cabral
authors.affiliation: Department of Otolaryngology, Faculty of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Yu
authors.initials: Y
authors.lastname: Matsumoto
authors.affiliation: Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Kazunori
authors.initials: K
authors.lastname: Nagasaka
authors.affiliation: Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Teikyo, Tokyo, Japan.
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Nakagawa
authors.affiliation: Department of Obstetrics and Gynecology, National Center for Global Health and Medicine, Tokyo, Japan.
authors.forename: Tetsu
authors.initials: T
authors.lastname: Yano
authors.affiliation: Department of Cellular and Organ Pathology, Graduate School of Medicine, Akita University, Akita, Japan.
authors.forename: Daichi
authors.initials: D
authors.lastname: Maeda
authors.affiliation: Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Katsutoshi
authors.initials: K
authors.lastname: Oda
authors.affiliation: Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Kei
authors.initials: K
authors.lastname: Kawana
authors.affiliation: Polymer Chemistry Division, Chemical Resources Laboratory, Tokyo Institute of Technology, Yokohama, Japan.
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Nishiyama
authors.affiliation: Department of Bioengineering, Graduate School of Engineering, The University of Tokyo, Tokyo, Japan.|Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.|Department of Materials Engineering, Graduate School of Engineering, The University of Tokyo, Tokyo, Japan.|Innovation Center of Nanomedicine, Kawasaki Institute of Industry Promotion, Kawasaki, Japan.
authors.forename: Kazunori
authors.initials: K
authors.lastname: Kataoka
authors.affiliation: Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Fujii
mesh_terms: D000818:Animals; D017209:Apoptosis; D045744:Cell Line, Tumor; D005260:Female; D007976:Leupeptins / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008823:Micelles; D061988:Proteasome Inhibitors / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D007976:Leupeptins; D008565:Membrane Proteins; D008823:Micelles; D061988:Proteasome Inhibitors; C480591:SCRIB protein, human; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde
keywords: Antineoplastic agents; benzyloxycarbonylleucyl-leucyl-leucine aldehyde; drug delivery system; nanomedicine; uterine cervical neoplasms