title: Self-assembled glycol chitosan nanoparticles for the sustained and prolonged delivery of antiangiogenic small peptide drugs in cancer therapy.
abstract: Antiangiogenic peptide drugs have received much attention in the fields of tumor therapy and tumor imaging because they show promise in the targeting of integrins such as alpha(v)beta(3) on angiogenic endothelial cells. However, systemic antiangiogenic peptide drugs have short half-lives in vivo, resulting in fast serum clearance via the kidney, and thus the therapeutic effects of such drugs remain modest. In this study, we prepared self-assembled glycol chitosan nanoparticles and explored whether this construct might function as a prolonged and sustained drug delivery system for RGD peptide, used as an antiangiogenic model drug in cancer therapy. Glycol chitosan hydrophobically modified with 5beta-cholanic acid (HGC) formed nanoparticles with a diameter of 230 nm, and RGD peptide was easily encapsulated into HGC nanoparticles (yielding RGD-HGC nanoparticles) with a high loading efficiency (>85%). In vitro work demonstrated that RGD-HGC showed prolonged and sustained release of RGD, lasting for 1 week. RGD-HGC also inhibited HUVEC adhesion to a beta ig-h3 protein-coated surface, indicating an antiangiogenic effect of the RGD peptide in the HGC nanoparticles. In an in vivo study, the antiangiogenic peptide drug formulation of RGD-HGC markedly inhibited bFGF-induced angiogenesis and decreased hemoglobin content in Matrigel plugs. Intratumoral administration of RGD-HGC significantly decreased tumor growth and microvessel density compared to native RGD peptide injected either intravenously or intratumorally, because the RGD-HGC formulation strongly enhanced the antiangiogenic and antitumoral efficacy of RGD peptide by affording prolonged and sustained RGD peptide delivery locally and regionally in solid tumors.
authors.affiliation: Biomedical Research Center, Korea Institute of Science and Technology, Seongbuk-Gu, Seoul, Republic of Korea.
authors.forename: Jong-Ho
authors.initials: JH
authors.lastname: Kim
authors.forename: Yoo-Shin
authors.initials: YS
authors.lastname: Kim
authors.forename: Kyeongsoon
authors.initials: K
authors.lastname: Park
authors.forename: Eunah
authors.initials: E
authors.lastname: Kang
authors.forename: Seulki
authors.initials: S
authors.lastname: Lee
authors.forename: Hae Yun
authors.initials: HY
authors.lastname: Nam
authors.forename: Kwangmeyung
authors.initials: K
authors.lastname: Kim
authors.forename: Jae Hyung
authors.initials: JH
authors.lastname: Park
authors.forename: Dae Yoon
authors.initials: DY
authors.lastname: Chi
authors.forename: Rang-Woon
authors.initials: RW
authors.lastname: Park
authors.forename: In-San
authors.initials: IS
authors.lastname: Kim
authors.forename: Kuiwon
authors.initials: K
authors.lastname: Choi
authors.forename: Ick
authors.initials: I
authors.lastname: Chan Kwon
mesh_terms: D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000737:chemistry; D000818:Animals; D048271:Chitosan / Q000737:chemistry*; D003692:Delayed-Action Preparations / Q000008:administration & dosage / Q000737:chemistry*; D004337:Drug Carriers / Q000008:administration & dosage / Q000737:chemistry*; D006018:Glycols / Q000008:administration & dosage / Q000737:chemistry; D008297:Male; D008422:Materials Testing; D008545:Melanoma / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D053758:Nanoparticles / Q000737:chemistry / Q000627:therapeutic use* / Q000648:ultrastructure; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000473:pathology; D009842:Oligopeptides / Q000008:administration & dosage* / Q000737:chemistry; D016896:Treatment Outcome
chemical_list: D020533:Angiogenesis Inhibitors; D003692:Delayed-Action Preparations; D004337:Drug Carriers; D006018:Glycols; D009842:Oligopeptides; C047981:arginyl-glycyl-aspartic acid; D048271:Chitosan