Targeted gene delivery by polyplex micelles with crowded PEG palisade and cRGD moiety for systemic treatment of pancreatic tumors

Zhishen Ge; Qixian Chen; Kensuke Osada; Xueying Liu; Theofilus A Tockary; Satoshi Uchida; Anjaneyulu Dirisala; Takehiko Ishii; Takahiro Nomoto; Kazuko Toh; Yu Matsumoto; Makoto Oba; Mitsunobu R Kano; Keiji Itaka; Kazunori Kataoka

doi:10.1016/j.biomaterials.2013.12.086

Targeted gene delivery by polyplex micelles with crowded PEG palisade and cRGD moiety for systemic treatment of pancreatic tumors

Biomaterials. 2014 Mar;35(10):3416-26. doi: 10.1016/j.biomaterials.2013.12.086. Epub 2014 Jan 15.

Authors

Zhishen Ge¹, Qixian Chen², Kensuke Osada³, Xueying Liu⁴, Theofilus A Tockary², Satoshi Uchida⁴, Anjaneyulu Dirisala⁵, Takehiko Ishii⁵, Takahiro Nomoto⁵, Kazuko Toh⁴, Yu Matsumoto⁴, Makoto Oba⁶, Mitsunobu R Kano⁷, Keiji Itaka⁴, Kazunori Kataoka⁸

Affiliations

¹ Department of Materials Engineering, Graduate School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656, Japan; CAS Key Laboratory of Soft Matter Chemistry, Department of Polymer Science and Engineering, University of Science and Technology of China, Hefei 230026, China.
² Department of Materials Engineering, Graduate School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656, Japan.
³ 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, Japan. Electronic address: [email protected].
⁴ 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.
⁵ Department of Bioengineering, Graduate School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656, Japan.
⁶ Department of Molecular Medicinal Sciences, Division of Pharmaceutical Chemistry, School of Pharmaceutical Sciences, Nagasaki University, 1-14 Bunkyo-machi, Nagasaki 852-8521, Japan.
⁷ Department of Pharmaceutical Biomedicine, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University, 1-1-1 Tsuhima-Naka, Kita-ku, Okayama 700-8530, Japan.
⁸ 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; 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. Electronic address: [email protected].

PMID: 24439417
DOI: 10.1016/j.biomaterials.2013.12.086

Abstract

Adequate retention in systemic circulation is the preliminary requirement for systemic gene delivery to afford high bioavailability into the targeted site. Polyplex micelle formulated through self-assembly of oppositely-charged poly(ethylene glycol) (PEG)-polycation block copolymer and plasmid DNA has gained tempting perspective upon its advantageous core-shell architecture, where outer hydrophilic PEG shell offers superior stealth behaviors. Aiming to promote these potential characters toward systemic applications, we strategically introduced hydrophobic cholesteryl moiety at the ω-terminus of block copolymer, anticipating to promote not only the stability of polyplex structure but also the tethered PEG crowdedness. Moreover, Mw of PEG in the PEGylated polyplex micelle was elongated up to 20 kDa for expecting further enhancement in PEG crowdedness. Furthermore, cyclic RGD peptide as ligand molecule to integrin receptors was installed at the distal end of PEG in order for facilitating targeted delivery to the tumor site as well as promoting cellular uptake and intracellular trafficking behaviors. Thus constructed cRGD conjugated polyplex micelle with the elevated PEG shielding was challenged to a modeled intractable pancreatic cancer in mice, achieving potent tumor growth suppression by efficient gene expression of antiangiogenic protein (sFlt-1) at the tumor site.

Keywords: DNA; Gene transfer; In vitro test; In vivo test; Micelle; Nanoparticle.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adenocarcinoma / drug therapy*
Animals
HeLa Cells
Humans
Mice
Micelles*
Oligopeptides / administration & dosage
Oligopeptides / therapeutic use*
Pancreatic Neoplasms / drug therapy*
Polyethylene Glycols / chemistry*
Transfection*

Substances

Micelles
Oligopeptides
Polyethylene Glycols
arginyl-glycyl-aspartic acid