Tumor uptake of the RGD dimeric probe (99m)Tc-G3-2P4-RGD2 is correlated with integrin αvβ3 expressed on both tumor cells and neovasculature

Bioconjug Chem. 2010 Mar 17;21(3):548-55. doi: 10.1021/bc900547d. Epub 2010 Feb 25.

Abstract

Integrin αvβ3 has been well-documented as one of the key players in the process of tumor angiogenesis. Radiolabeled RGD (Arg-Gly-Asp) peptides that specifically target integrin αvβ3 have great potential for tumor early detection and noninvasively monitoring the status of tumor angiogenesis. We developed a cyclic RGD dimeric probe (99m)Tc-HYNIC-Gly3-E[PEG4-c(RGDfK)]2 ((99m)Tc-G3-2P4-RGD2) (using tricine and TPPTS as the coligands, TPPTS = trisodium triphenylphosphine-3,3',3''-trisulfonate), and investigated whether it could be used to noninvasively visualize and quantify integrin αvβ3 expression in vivo. HYNIC-Gly3-E[PEG4-c(RGDfK)]2 was synthesized and labeled with (99m)Tc. The biodistribution and planar γ-imaging studies of (99m)Tc-G3-2P4-RGD2 were performed in both U87MG (human integrin αvβ3 positive/murine integrin αvβ3 positive) and HT-29 (human integrin αvβ3 negligible /murine integrin αvβ3 positive) tumor-bearing nude mouse models. The correlation of (99m)Tc-G3-2P4-RGD2 tumor uptake values (measured by ex vivo biodistribution) with expression levels of human integrin αvβ3 or murine integrin αvβ3 (measured by Western blot) were determined in U87MG and HT-29 tumor models, respectively. (99m)Tc-G3-2P4-RGD2 exhibited increased receptor binding affinity and in vivo tumor uptake as compared with previously reported RGD dimeric tracer (99m)Tc-RGD2 (without Gly3 and PEG4 spacers). The tumor uptake of (99m)Tc-G3-2P4-RGD2 was related to the expression levels of both human integrin αvβ3 (expressed on tumor cells) and murine integrin αvβ3 (expressed on newborn tumor vasculature). Our results demonstrate that (99m)Tc-G3-2P4-RGD2 is a useful agent for integrin αvβ3 imaging. The relationship between (99m)Tc-G3-2P4-RGD2 uptake and integrin αvβ3 expression level as determined by this study would provide useful information for clinical translation of RGD probes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Dimerization
  • Female
  • Fluorescent Dyes / analysis
  • HT29 Cells
  • Humans
  • Integrin alphaVbeta3 / analysis
  • Integrin alphaVbeta3 / metabolism*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Neoplasms / blood supply*
  • Neoplasms / metabolism*
  • Neovascularization, Pathologic / metabolism*
  • Oligopeptides / analysis
  • Oligopeptides / chemistry
  • Oligopeptides / metabolism*
  • Oligopeptides / pharmacokinetics*
  • Organotechnetium Compounds / analysis*
  • Organotechnetium Compounds / chemistry
  • Organotechnetium Compounds / metabolism
  • Organotechnetium Compounds / pharmacokinetics
  • Peptides, Cyclic / analysis*
  • Peptides, Cyclic / chemistry
  • Peptides, Cyclic / metabolism
  • Peptides, Cyclic / pharmacokinetics
  • Tissue Distribution
  • Tumor Cells, Cultured

Substances

  • Fluorescent Dyes
  • Integrin alphaVbeta3
  • Oligopeptides
  • Organotechnetium Compounds
  • Peptides, Cyclic
  • technetium 99m HYNIC-Gly3-E(PEG4-c(RGDfK))
  • arginyl-glycyl-aspartic acid