Targeted gene delivery by polyplex micelles with crowded PEG palisade and cRGD moiety for systemic treatment of pancreatic tumors
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- 作者：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
- 关键词：DNA ; Micelle ; Nanoparticle ; Gene transfer ; In vitro test ; In vivo test
- 刊名：Biomaterials
- 出版年：March, 2014
- 年：2014
- 卷：35
- 期：10
- 页码：3416-3426
- 全文大小：2143 K
文摘
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 蠅-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聽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.