title: Tumor uptake of the RGD dimeric probe (99m)Tc-G3-2P4-RGD2 is correlated with integrin αvβ3 expressed on both tumor cells and neovasculature.
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.
authors.affiliation: Medical Isotopes Research Center, Peking University, Beijing 100191, China, Department of Nuclear Medicine, Peking Union Medical College Hospital, Beijing 100730, China, and School of Health Sciences, Purdue University, West Lafayette, Indiana 47907.
authors.forename: Zhaofei
authors.initials: Z
authors.lastname: Liu
authors.forename: Bing
authors.initials: B
authors.lastname: Jia
authors.forename: Jiyun
authors.initials: J
authors.lastname: Shi
authors.forename: Xiaona
authors.initials: X
authors.lastname: Jin
authors.forename: Huiyun
authors.initials: H
authors.lastname: Zhao
authors.forename: Fang
authors.initials: F
authors.lastname: Li
authors.forename: Shuang
authors.initials: S
authors.lastname: Liu
authors.forename: Fan
authors.initials: F
authors.lastname: Wang
mesh_terms: D000818:Animals; D019281:Dimerization; D005260:Female; D005456:Fluorescent Dyes / Q000032:analysis; D019073:HT29 Cells; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000032:analysis / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009369:Neoplasms / Q000098:blood supply* / Q000378:metabolism*; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D009842:Oligopeptides / Q000032:analysis / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics*; D015609:Organotechnetium Compounds / Q000032:analysis* / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics; D010456:Peptides, Cyclic / Q000032:analysis* / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics; D014018:Tissue Distribution; D014407:Tumor Cells, Cultured
chemical_list: D005456:Fluorescent Dyes; D039302:Integrin alphaVbeta3; D009842:Oligopeptides; D015609:Organotechnetium Compounds; D010456:Peptides, Cyclic; C000597216:technetium 99m HYNIC-Gly3-E(PEG4-c(RGDfK)); C047981:arginyl-glycyl-aspartic acid