title: Effect of shear stress on structure and function of polyplex micelles from poly(ethylene glycol)-poly(l-lysine) block copolymers as systemic gene delivery carrier.
abstract: Structural stability of polyplex micelles (PMs), prepared from plasmid DNA (pDNA) and poly(ethylene glycol)-b-poly(l-lysine) block catiomer (PEG-PLys), was evaluated in terms of their resistance against shear stress. When exposed to shear stress at magnitudes typically present in the blood stream, structural deterioration was observed in PMs owing to the partial removal of PEG-PLys strands. Eventually, impaired PEG coverage of the polyplex core led to accelerated degradation by nucleases, implying that structural deterioration by shear stress in blood stream may be a major cause of rapid clearance of PMs from blood circulation. To address this issue, introduction of disulfide crosslinking into the PM core was shown to be an efficient strategy, which successfully mitigated unfavorable effects of shear stress. Furthermore, improved in vivo blood retention profile and subsequently enhanced antitumor efficacy in systemic treatment of pancreatic adenocarcinoma were confirmed for the crosslinked PMs loaded with pDNA encoding an anti-angiogenic protein, suggesting that high stability under the shear stress during blood circulation may be a critical factor in systemically applicable gene delivery systems.
authors.affiliation: Department of Materials Engineering, Graduate School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8656, Japan.
authors.forename: Kaori M
authors.initials: KM
authors.lastname: Takeda
authors.affiliation: Department of Materials Engineering, Graduate School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8656, Japan; Innovation Center of NanoMedicine (iCONM), Kawasaki Institute of Industrial Promotion, 3-25-14 Tonomachi, Kawasaki-ku, Kawasaki, 210-0821, Japan. Electronic address: yamasaki@bmw.t.u-tokyo.ac.jp.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Yamasaki
authors.affiliation: 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; Innovation Center of NanoMedicine (iCONM), Kawasaki Institute of Industrial Promotion, 3-25-14 Tonomachi, Kawasaki-ku, Kawasaki, 210-0821, Japan.
authors.forename: Anjaneyulu
authors.initials: A
authors.lastname: Dirisala
authors.affiliation: Department of Materials Engineering, Graduate School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8656, Japan.
authors.forename: Sorato
authors.initials: S
authors.lastname: Ikeda
authors.affiliation: Department of Materials Engineering, Graduate School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8656, Japan; Innovation Center of NanoMedicine (iCONM), Kawasaki Institute of Industrial Promotion, 3-25-14 Tonomachi, Kawasaki-ku, Kawasaki, 210-0821, Japan.
authors.forename: Theofilus A
authors.initials: TA
authors.lastname: Tockary
authors.affiliation: Innovation Center of NanoMedicine (iCONM), Kawasaki Institute of Industrial Promotion, 3-25-14 Tonomachi, Kawasaki-ku, Kawasaki, 210-0821, Japan.
authors.forename: Kazuko
authors.initials: K
authors.lastname: Toh
authors.affiliation: Department of Bioengineering, Graduate School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8656, Japan; Japan Science and Technology Agency, PRESTO, 4-1-8 Honcho, Kawaguchi, Saitama, 332-0012, Japan; Innovation Center of NanoMedicine (iCONM), Kawasaki Institute of Industrial Promotion, 3-25-14 Tonomachi, Kawasaki-ku, Kawasaki, 210-0821, Japan. Electronic address: osada@bmw.t.u-tokyo.ac.jp.
authors.forename: Kensuke
authors.initials: K
authors.lastname: Osada
authors.affiliation: 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; 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 (iCONM), Kawasaki Institute of Industrial Promotion, 3-25-14 Tonomachi, Kawasaki-ku, Kawasaki, 210-0821, Japan. Electronic address: kataoka@bmw.t.u-tokyo.ac.jp.
authors.forename: Kazunori
authors.initials: K
authors.lastname: Kataoka
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000473:pathology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D001775:Blood Circulation; D045744:Cell Line, Tumor; D003432:Cross-Linking Reagents / Q000737:chemistry; D004247:DNA / Q000235:genetics / Q000648:ultrastructure; D042003:DNA Packaging; D018014:Gene Transfer Techniques; D006801:Humans; D008239:Lysine / Q000031:analogs & derivatives* / Q000737:chemistry; D008807:Mice, Inbred BALB C; D008823:Micelles; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000473:pathology; D010957:Plasmids / Q000235:genetics / Q000648:ultrastructure; D011092:Polyethylene Glycols / Q000737:chemistry*; D033081:Shear Strength; D014162:Transfection
chemical_list: D000970:Antineoplastic Agents; D003432:Cross-Linking Reagents; D008823:Micelles; C092361:poly(ethylene glycol) lysine copolymer; D011092:Polyethylene Glycols; D004247:DNA; D008239:Lysine
keywords: Nonviral gene delivery; Poly(ethylene glycol); Polyplex micelle; Shear stress; Systemic administration