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Favorable Biokinetic and Tumor-Targeting Properties of ^99mTc-Labeled Glucosamino RGD and Effect of Paclitaxel Therapy

¹ Department of Nuclear Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea; and ² Department of Chemistry, Inha University, Inchun, Korea

Correspondence: For correspondence contact: Kyung-Han Lee, MD, Department of Nuclear Medicine, Samsung Medical Center, 50 Ilwondong, Kangnamgu, Seoul, Korea. E-mail: khnm.lee{at}samsung.com

Compared with the recent advancements in radiohalogenated Arg-Gly-Asp (RGD) peptides for _vß₃-targeted imaging, there has been limited success with ^99mTc-labeled RGD compounds. In this article, we describe the favorable in vivo kinetics and tumor-imaging properties of a novel ^99mTc-RGD compound that contains a glucosamine moiety. Methods: Glucosamino ^99mTc-D-c(RGDfK) was prepared by incorporating ^99mTc(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 ^99mTc-D-c(RGDfK) uptake and Western blots of _v integrin expression were analyzed at day 14. Results: Glucosamino ^99mTc-D-c(RGDfK) binding to endothelial cells was dose-dependently inhibited by excess RGD. Biodistribution in mice showed rapid blood clearance of glucosamino ^99mTc-D-c(RGDfK), with substantially lower liver uptake and higher tumor uptake compared with ¹²⁵I-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. -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 ^99mTc-D-c(RGDfK) uptake, which correlated significantly with tumor _v integrin expression levels. Conclusion: Glucosamino ^99mTc-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 -cameras and high availability and excellent imaging characteristics of ^99mTc, glucosamino ^99mTc-D-c(RGDfK) may be an attractive alternative to radiohalogenated RGD peptides for angiogenesis-imaging research.

Key Words: RGD peptide • ^99mTc • integrin • tumor • angiogenesis • paclitaxel

COPYRIGHT © 2006 by the Society of Nuclear Medicine, Inc.

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