title: RGD peptide-conjugated multimodal NaGdF4:Yb3+/Er3+ nanophosphors for upconversion luminescence, MR, and PET imaging of tumor angiogenesis.
abstract: Multimodal nanoparticles have been extensively studied for target-specific imaging and therapy of various diseases, including cancer. In this study, radiolabeled arginine-glycine-aspartic acid (RGD)-functionalized Er(3+)/Yb(3+) co-doped NaGdF(4) upconversion nanophosphors (UCNPs) were synthesized and evaluated as a multimodal PET/MR/optical probe with tumor angiogenesis-specific targeting properties.
  
  
  METHODS
  A dimeric cyclic RGDyk ((cRGDyk)(2)) peptide was conjugated to polyacrylic acid-coated NaGdF(4):Yb(3+)/Er(3+) UCNPs along with polyethylene glycol molecules and was consecutively radiolabeled with (124)I. In vitro cytotoxicity testing was performed for 3 d. Upconversion luminescence imaging of (cRGDyk)(2)-UCNP was performed on U87MG cells with a laboratory-made confocal microscope. In vivo small-animal PET and clinical 3-T T1-weighted MR imaging of (124)I-labeled RGD-functionalized UCNPs was acquired with or without blocking of cyclic RGD peptide in a U87MG tumor model. Inductively coupled plasma mass spectrometry and biologic transmission electron microscopy were done to evaluate gadolinium concentration and UCNP localization, respectively.
  
  
  RESULTS
  Polymer-coated UCNPs and dimeric RGD-conjugated UCNPs were monodispersely synthesized, and those of hydrodynamic size were 30 ± 8 nm and 32 ± 9 nm, respectively. (cRGDyk)(2)-UCNPs have a low cytotoxic effect on cells. Upconversion luminescence signals of (cRGDyk)(2)-UCNP were specifically localized on the surface of U87MG cells. (124)I-c(RGDyk)(2)-UCNPs specifically accumulated in U87MG tumors (2.8 ± 0.8 vs. 1.3 ± 0.4 percentage injected dose per gram in the blocking experiment), and T1-weighted MR images showed significant positive contrast enhancement in U87MG tumors. Tumor localization of (124)I-c(RGDyk)(2)-UCNPs was confirmed by inductively coupled plasma mass spectrometry and biologic transmission electron microscopy analysis.
  
  
  CONCLUSIONS
  These results suggest that (124)I-labeled RGD-functionalized UCNPs have high specificity for α(v)β(3) integrin-expressing U87MG tumor cells and xenografted tumor models. Multimodal UCNPs can be used as a platform nanoparticle with multimodal imaging for cancer-specific diagnoses.
authors.affiliation: Nano/Bio Chemistry Laboratory, Institut Pasteur Korea, Gyeonggi-do, South Korea.
authors.forename: Junghan
authors.initials: J
authors.lastname: Lee
authors.forename: Tae Sup
authors.initials: TS
authors.lastname: Lee
authors.forename: Jiyoung
authors.initials: J
authors.lastname: Ryu
authors.forename: Sukmin
authors.initials: S
authors.lastname: Hong
authors.forename: Moonsik
authors.initials: M
authors.lastname: Kang
authors.forename: Kangbin
authors.initials: K
authors.lastname: Im
authors.forename: Joo Hyun
authors.initials: JH
authors.lastname: Kang
authors.forename: Sang Moo
authors.initials: SM
authors.lastname: Lim
authors.forename: Sun
authors.initials: S
authors.lastname: Park
authors.forename: Rita
authors.initials: R
authors.lastname: Song
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D019281:Dimerization; D004871:Erbium / Q000737:chemistry*; D005240:Feasibility Studies; D005459:Fluorides / Q000737:chemistry*; D005682:Gadolinium / Q000737:chemistry*; D005909:Glioblastoma / Q000098:blood supply* / Q000175:diagnosis / Q000000981:diagnostic imaging / Q000473:pathology; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000378:metabolism; D007457:Iodine Radioisotopes; D049408:Luminescent Agents / Q000737:chemistry; D008163:Luminescent Measurements; D008279:Magnetic Resonance Imaging; D051379:Mice; D057054:Molecular Imaging / Q000379:methods*; D049329:Nanostructures / Q000633:toxicity; D009389:Neovascularization, Pathologic; D009842:Oligopeptides / Q000737:chemistry* / Q000633:toxicity; D011092:Polyethylene Glycols / Q000737:chemistry; D049268:Positron-Emission Tomography; D015018:Ytterbium / Q000737:chemistry*
chemical_list: D039302:Integrin alphaVbeta3; D007457:Iodine Radioisotopes; D049408:Luminescent Agents; D009842:Oligopeptides; D011092:Polyethylene Glycols; D004871:Erbium; C047981:arginyl-glycyl-aspartic acid; D005682:Gadolinium; D015018:Ytterbium; D005459:Fluorides