Abstract
Dynamic fluorescence images were obtained from xenografts bearing a subcutaneous human Kaposi's sarcoma (KS1767) immediately following the intravenous injection of an integrin-receptor targeting Cy5.5-c(KRGDf) at a dose ranging from 0.75 to 6 nmol/mouse. The fluorescence images were acquired using an intensified charge-coupled device system and were analyzed with a three-compartment pharmacokinetic (PK) model to determine uptake parameters in the tumor and normal tissue regions of interest as a function of administered dose. Our results show that the uptake of Cy5.5-c(KRGDf) in tumor regions were: (i) significantly greater than the contralateral normal tissue regions; (ii) linearly increased with dose of Cy5.5-c(KRGDf) up to 1.5 nmol/mouse; and (iii) blocked by preinjection of c(KRGDf). Above doses of 1.5 nmol/mouse, the uptake no longer increased with dose, suggesting integrin receptor saturation. In normal tissues, the PK uptake parameters were not influenced by Cy5.5-c(KRGDf) dose nor by the preadministration of c(KRGDf).
Highlights
Integrins are a large family of heterodimeric glycoproteins consisting of two subunits, a and b [1]
It has been shown that antagonists of avb3 induce tumor regression and apoptosis of angiogenic endothelial cells [14 – 16], which implies that the integrin avb3 may be a viable marker for the tumor growth and spread
To date there are no standardized fluorescence imaging systems and newly reported evidence from our laboratories suggests that target-to-background (TBR) values generated from intensity-based fluorescence imaging systems which produce planar images may be more likely dependent upon instrumentation than on the selectivity of the targeting contrast agent [25]
Summary
Integrins are a large family of heterodimeric glycoproteins consisting of two subunits, a and b [1]. Avb, known as a vitronectin receptor, is recently reported to play an important role in tumor metastasis [2 – 5] and angiogenesis [6], which is the growth of new blood vessels from preexisting vasculatures during tumor growth [3,7,8]. This integrin is expressed on tumor cells during angiogenesis [9,10,11,12,13,14]. To date there are no standardized fluorescence imaging systems and newly reported evidence from our laboratories suggests that target-to-background (TBR) values generated from intensity-based fluorescence imaging systems which produce planar images may be more likely dependent upon instrumentation than on the selectivity of the targeting contrast agent [25]
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