Favorable biokinetic and tumor-targeting properties of 99mTc-labeled glucosamino RGD and effect of paclitaxel therapy.
Compared with the recent advancements in radiohalogenated Arg-Gly-Asp (RGD) peptides for alpha(v)beta(3)-targeted imaging, there has been limited success with (99m)Tc-labeled RGD compounds. In this article, we describe the favorable in vivo kinetics and tumor-imaging properties of a novel (99m)Tc-RGD compound that contains a glucosamine moiety.


METHODS
Glucosamino (99m)Tc-d-c(RGDfK) was prepared by incorporating (99m)Tc(CO)(3) to the glucosamino peptide precursor in high radiochemical yield. Cell-binding characteristics were tested on human endothelial cells. Mice bearing RR1022 fibrosarcoma and Lewis lung carcinoma (LLC) tumors were used for in vivo biodistribution and blocking experiments and for imaging studies. Separate LLC-bearing mice underwent antiangiogenic therapy with 0, 20, or 40 mg of paclitaxel per kilogram of body weight every 2 d. Tumor volume was serially monitored, and tumor glucosamino (99m)Tc-d-c(RGDfK) uptake and Western blots of alpha(v) integrin expression were analyzed at day 14.


RESULTS
Glucosamino (99m)Tc-d-c(RGDfK) binding to endothelial cells was dose-dependently inhibited by excess RGD. Biodistribution in mice showed rapid blood clearance of glucosamino (99m)Tc-d-c(RGDfK), with substantially lower liver uptake and higher tumor uptake compared with (125)I-c(RGD(I)yV). Tumor uptake was 1.03 +/- 0.21 and 1.18 +/- 0.26 %ID/g at 1 h and 0.85 +/- 0.05 and 0.89 +/- 0.28 %ID/g at 4 h for sarcomas and carcinomas, respectively. Excess RGD blocked uptake by 76.5% and 70.2% for the respective tumors. gamma-Camera imaging allowed clear tumor visualization, with an increase of sarcoma-to-thigh count ratios from 5.5 +/- 0.7 at 1 h to 10.1 +/- 2.2 at 4 h and sustained carcinoma-to-thigh count ratios from 4 to 17 h. Pretreatment with excess cRGDyV significantly reduced tumor contrast on images. Paclitaxel therapy in LLC tumor-bearing mice significantly retarded tumor growth. This was accompanied by a corresponding reduction of tumor glucosamino (99m)Tc-d-c(RGDfK) uptake, which correlated significantly with tumor alpha(v) integrin expression levels.


CONCLUSIONS
Glucosamino (99m)Tc-d-c(RGDfK) has favorable in vivo biokinetics and tumor-imaging properties and may be useful for noninvasive evaluation of tumor integrin expression and response to antiangiogenic therapeutics. Because of the wide accessibility of gamma-cameras and high availability and excellent imaging characteristics of (99m)Tc, glucosamino (99m)Tc-d-c(RGDfK) may be an attractive alternative to radiohalogenated RGD peptides for angiogenesis-imaging research.
Jung
Kyung-Ho
KH
Department of Nuclear Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Kangnam-Gu, Seoul, Korea.
Lee
Kyung-Han
KH
Paik
Jin-Young
JY
Ko
Bong-Ho
BH
Bae
Jun-Sang
JS
Lee
Byung Chul
BC
Sung
Hyun Ju
HJ
Kim
Dong Hyun
DH
Choe
Yearn Seong
YS
Chi
Dae Yoon
DY
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D016503:Drug Delivery Systems / Q000379:methods; D005354:Fibrosarcoma / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007700:Kinetics; D008297:Male; D008657:Metabolic Clearance Rate / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009842:Oligopeptides / Q000493:pharmacokinetics*; D009928:Organ Specificity / Q000187:drug effects; D017239:Paclitaxel / Q000008:administration & dosage*; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D051381:Rats; D013667:Technetium / Q000493:pharmacokinetics*; D014018:Tissue Distribution / Q000187:drug effects; D016896:Treatment Outcome
D000972:Antineoplastic Agents, Phytogenic; D009842:Oligopeptides; D019275:Radiopharmaceuticals; D013667:Technetium; C047981:arginyl-glycyl-aspartic acid; D017239:Paclitaxel