title: Specific targeting of angiogenesis in lung cancer with RGD-conjugated ultrasmall superparamagnetic iron oxide particles using a 4.7T magnetic resonance scanner.
abstract: BACKGROUND
  Angiogenesis is an essential step for tumor development and metastasis. The cell adhesion molecule avβ3 integrin plays an important role in angiogenesis and is a specific marker of tumor angiogenesis. A novel avβ3 integrin- targeted magnetic resonance (MR) imaging contrast agent utilizing Arg-Gly-Asp (RGD) and ultrasmall superparamagnetic iron oxide particles (USPIO) (referred to as RGD-USPIO) was designed and its uptake by endothelial cells was assessed both in vitro and in vivo to evaluate the angiogenic profile of lung cancer.
  
  
  METHODS
  USPIO were coated with -NH3+ and conjugated with RGD peptides. Prussian blue staining was performed to evaluate the specific uptake of RGD-USPIO by human umbilical vein endothelial cells (HUVECs). Targeted uptake and subcellular localization of RGD-USPIO in HUVECs were confirmed by transmission electron microscopy (TEM). The ability of RGD-USPIO to noninvasively assess avβ3 integrin positive vessels in lung adenocarcinoma A549 tumor xenografts was evaluated with a 4.7T MR scanner. Immunohistochemistry was used to detect avβ3 integrin expression and vessel distribution in A549 tumor xenografts.
  
  
  RESULTS
  HUVECs internalized RGD-USPIO significantly more than plain USPIO. The uptake of RGD-USPIO by HUVECs could be competitively inhibited by addition of free RGD. A significant decrease in T2 signal intensity (SI) was observed at the periphery of A549 tumor xenografts at 30 minutes (P < 0.05) and 2 hours (P < 0.01) after RGD-USPIO was injected via the tail vein. Angiogenic blood vessels were mainly distributed in the periphery of tumor xenografts with positive avβ3 integrin expression.
  
  
  CONCLUSIONS
  RGD-USPIO could specifically label avβ3 integrin and be taken up by HUVECs. This molecular MR imaging contrast agent can specifically evaluate the angiogenic profile of lung cancer using a 4.7T MR scanner.
authors.affiliation: Cancer Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China.
authors.forename: Can
authors.initials: C
authors.lastname: Liu
authors.forename: Dong-Bo
authors.initials: DB
authors.lastname: Liu
authors.forename: Guo-Xian
authors.initials: GX
authors.lastname: Long
authors.forename: Jun-Feng
authors.initials: JF
authors.lastname: Wang
authors.forename: Qi
authors.initials: Q
authors.lastname: Mei
authors.forename: Guang-Yuan
authors.initials: GY
authors.lastname: Hu
authors.forename: Hong
authors.initials: H
authors.lastname: Qiu
authors.forename: Guo-Qing
authors.initials: GQ
authors.lastname: Hu
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003911:Dextrans / Q000627:therapeutic use*; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000032:analysis; D008175:Lung Neoplasms / Q000098:blood supply / Q000188:drug therapy*; D008279:Magnetic Resonance Imaging; D058185:Magnetite Nanoparticles / Q000627:therapeutic use*; D051379:Mice; D008807:Mice, Inbred BALB C; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D009842:Oligopeptides / Q000627:therapeutic use*
chemical_list: D003911:Dextrans; D039302:Integrin alphaVbeta3; D058185:Magnetite Nanoparticles; D009842:Oligopeptides; C097921:ferumoxtran-10; C047981:arginyl-glycyl-aspartic acid