title: Bioreducible branched poly(modified nona-arginine) cell-penetrating peptide as a novel gene delivery platform.
abstract: Cell-penetrating peptides (CPPs) have been widely used to deliver nucleic acid molecules. Generally, CPPs consisting of short amino acid sequences have a linear structure, resulting in a weak complexation and low transfection efficacy. To overcome these drawbacks, a novel type of CPP is required to enhance the delivery efficacy while maintaining its safe use at the same time. Herein, we report that a bioreducible branched poly-CPP structure capable of responding to reducing conditions attained both outstanding delivery effectiveness and selective gene release in carcinoma cells. Branched structures provide unusually strong electrostatic attraction between DNA and siRNA molecules, thereby improving the transfection capability through a tightly condensed form. We designed a modified type of nona-arginine (mR9) and synthesized a branched-mR9 (B-mR9) using disulfide bonds. A novel B-mR9/pDNA polyplex exhibited redox-cleavability and high transfection efficacy compared to conventional CPPs, with higher cell viability as well. B-mR9/VEGF siRNA polyplex exhibited significant serum stability and high gene-silencing effects in vitro. Furthermore, the B-mR9 polyplex showed outstanding tumor accumulation and inhibition ability in vivo. The results suggest that the bioreducible branched poly CPP has great potential as a gene delivery platform.
authors.affiliation: Department of Chemical and Biomolecular Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 305-701, Republic of Korea.
authors.forename: Jisang
authors.initials: J
authors.lastname: Yoo
authors.affiliation: Department of Chemical and Biomolecular Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 305-701, Republic of Korea.
authors.forename: DaeYong
authors.initials: D
authors.lastname: Lee
authors.affiliation: Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 305-701, Republic of Korea.
authors.forename: Vipul
authors.initials: V
authors.lastname: Gujrati
authors.affiliation: Department of Chemical and Biomolecular Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 305-701, Republic of Korea.
authors.forename: N Sanoj
authors.initials: NS
authors.lastname: Rejinold
authors.affiliation: Department of Biomedical Science and BK21 PLUS Centre for Creative Biomedical Scientists, Chonnam National University Medical School, 160 Baekseo-ro, Gwangju 501-746, Republic of Korea.
authors.forename: Kamali Manickavasagam
authors.initials: KM
authors.lastname: Lekshmi
authors.affiliation: Department of Biomedical Science and BK21 PLUS Centre for Creative Biomedical Scientists, Chonnam National University Medical School, 160 Baekseo-ro, Gwangju 501-746, Republic of Korea.
authors.forename: Saji
authors.initials: S
authors.lastname: Uthaman
authors.affiliation: Department of Chemical and Biomolecular Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 305-701, Republic of Korea.
authors.forename: Chanuk
authors.initials: C
authors.lastname: Jeong
authors.affiliation: Department of Biomedical Science and BK21 PLUS Centre for Creative Biomedical Scientists, Chonnam National University Medical School, 160 Baekseo-ro, Gwangju 501-746, Republic of Korea.
authors.forename: In-Kyu
authors.initials: IK
authors.lastname: Park
authors.affiliation: Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 305-701, Republic of Korea.
authors.forename: Sangyong
authors.initials: S
authors.lastname: Jon
authors.affiliation: Department of Chemical and Biomolecular Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 305-701, Republic of Korea. Electronic address: dohnanyi@kaist.ac.kr.
authors.forename: Yeu-Chun
authors.initials: YC
authors.lastname: Kim
mesh_terms: D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives*; D002470:Cell Survival; D057846:Cell-Penetrating Peptides / Q000737:chemistry*; D004247:DNA / Q000008:administration & dosage* / Q000235:genetics; D005260:Female; D018014:Gene Transfer Techniques; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010957:Plasmids / Q000008:administration & dosage* / Q000235:genetics; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000235:genetics; D014162:Transfection; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics
chemical_list: D057846:Cell-Penetrating Peptides; D034741:RNA, Small Interfering; D042461:Vascular Endothelial Growth Factor A; D004247:DNA; D001120:Arginine
keywords: Bioreducible; Branched structure; Cell-penetrating peptide (CPP); Gene delivery; VEGF siRNA; pGFP