title: Improving drug potency and efficacy by nanocarrier-mediated subcellular targeting.
abstract: Nanocarrier-mediated drug targeting is an emerging strategy for cancer therapy and is being used, for example, with chemotherapeutic agents for ovarian cancer. Nanocarriers are selectively accumulated in tumors as a result of their enhanced permeability and retention of macromolecules, thereby enhancing the antitumor activity of the nanocarrier-associated drugs. We investigated the real-time subcellular fate of polymeric micelles incorporating (1,2-diaminocyclohexane) platinum(II) (DACHPt/m), the parent complex of oxaliplatin, in tumor tissues by fluorescence-based assessment of their kinetic stability. These observations revealed that DACHPt/m was extravasated from blood vessels to the tumor tissue and dissociated inside each cell. Furthermore, DACHPt/m selectively dissociated within late endosomes, enhancing drug delivery to the nearby nucleus relative to free oxaliplatin, likely by circumvention of the cytoplasmic detoxification systems such as metallothionein and methionine synthase. Thus, these drug-loaded micelles exhibited higher antitumor activity than did oxaliplatin alone, even against oxaliplatin-resistant tumors. These findings suggest that nanocarriers targeting subcellular compartments may have considerable benefits in clinical applications.
authors.affiliation: Department of Bioengineering, Graduate School of Engineering, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656, Japan.
authors.forename: Mami
authors.initials: M
authors.lastname: Murakami
authors.forename: Horacio
authors.initials: H
authors.lastname: Cabral
authors.forename: Yu
authors.initials: Y
authors.lastname: Matsumoto
authors.forename: Shourong
authors.initials: S
authors.lastname: Wu
authors.forename: Mitsunobu R
authors.initials: MR
authors.lastname: Kano
authors.forename: Takao
authors.initials: T
authors.lastname: Yamori
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Nishiyama
authors.forename: Kazunori
authors.initials: K
authors.lastname: Kataoka
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D015153:Blotting, Western; D045744:Cell Line, Tumor; D004337:Drug Carriers / Q000737:chemistry* / Q000378:metabolism; D016503:Drug Delivery Systems / Q000379:methods*; D005260:Female; D019073:HT29 Cells; D006415:Hematoporphyrins / Q000008:administration & dosage; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009369:Neoplasms / Q000188:drug therapy; D009944:Organoplatinum Compounds / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D000077150:Oxaliplatin; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D000970:Antineoplastic Agents; D004337:Drug Carriers; D006415:Hematoporphyrins; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; C039137:O,O'-diacetylhematoporphyrin