title: Molecular logistics using cytocleavable polyrotaxanes for the reactivation of enzymes delivered in living cells.
abstract: The intracellular delivery of enzymes is an essential methodology to extend their therapeutic application. Herein, we have developed dissociable supermolecule-enzyme polyelectrolyte complexes based on reduction-cleavable cationic polyrotaxanes (PRXs) for the reactivation of delivered enzymes. These PRXs are characterized by their supramolecular frameworks of a polymeric chain threading into cyclic molecules, which can form polyelectrolyte complexes with anionic enzymes while retaining their three dimensional structure, although their enzymatic activity is reduced. Upon the addition of a reductant, the PRXs dissociate into their constituent molecules and release the enzymes, resulting in a complete recovery of enzymatic activity. Under the intracellular environment, the PRX-based enzyme complexes showed the highest intracellular enzymatic activity and efficient activation of anticancer prodrugs to induce cytotoxic effects in comparison with the non-dissociable complexes and the commercial cell-penetrating peptide-based reagents. Thus, the intracellularly dissociable supermolecules are an attractive system for delivering therapeutic enzymes into living cells.
authors.affiliation: Department of Organic Biomaterials, Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, 2-3-10 Kanda-Surugadai, Chiyoda, Tokyo 101-0062, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Tamura
authors.forename: Go
authors.initials: G
authors.lastname: Ikeda
authors.forename: Ji-Hun
authors.initials: JH
authors.lastname: Seo
authors.forename: Koji
authors.initials: K
authors.lastname: Tsuchiya
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Yajima
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Sasaki
authors.forename: Kazunari
authors.initials: K
authors.lastname: Akiyoshi
authors.forename: Nobuhiko
authors.initials: N
authors.lastname: Yui
mesh_terms: D000970:Antineoplastic Agents / Q000378:metabolism; D002460:Cell Line; D003505:Cyclodextrins / Q000737:chemistry; D004337:Drug Carriers / Q000737:chemistry; D016503:Drug Delivery Systems; D004789:Enzyme Activation; D004798:Enzymes / Q000008:administration & dosage*; D006801:Humans; D046911:Macromolecular Substances / Q000737:chemistry / Q000378:metabolism; D010084:Oxidation-Reduction; D020442:Poloxamer / Q000737:chemistry; D011108:Polymers / Q000737:chemistry; D011355:Prodrugs / Q000737:chemistry / Q000378:metabolism; D043862:Rotaxanes / Q000737:chemistry; D001616:beta-Galactosidase / Q000008:administration & dosage
chemical_list: D000970:Antineoplastic Agents; D003505:Cyclodextrins; D004337:Drug Carriers; D004798:Enzymes; D046911:Macromolecular Substances; D011108:Polymers; D011355:Prodrugs; D043862:Rotaxanes; C475673:polyrotaxane; D020442:Poloxamer; D001616:beta-Galactosidase