In vivo MR/optical imaging for gastrin releasing peptide receptor of prostate cancer tumor using Gd-TTDA-NP-BN-Cy5.5

Abstract

Magnetic resonance imaging (MRI) has become the leading imaging tool for providing fine anatomical and physiology details. Optical imaging is offering a sensitive and specific method for in vivo molecular imaging of targeting molecules. The goal of this study is to design, synthesize, and characterize a new target-specific dual contrast agent for MR and optical imaging. Hence, [Gd(TTDA-NP)(H(2)O)](2-) was prepared and characterized. In addition, an 8-amino acid Bombesin analogue (BN) peptide substrate, which can target prostate, breast, and colon cancer, was synthesized by solid-phase peptide synthesis and subsequently conjugated with [Gd(TTDA-NP)(H(2)O)](2-) to form BN conjugated Gd-TTDA-NP-BN. The water-exchange rate (ke(ex)(298)) for [Gd(TTDA-NP)(H(2)O)](2-) (110 x 10(6) s(-1)) is significantly higher than that of [Gd(DTPA) (H(2)O)](2-) complex and the rotational correlation time (tau(R)) for [Gd(TTDA-NP)(H(2)O)](2-) (145 ps) is also higher than those of [Gd(TTDA)(H(2)O)](2-) (104 ps) and [Gd(DTPA)(H(2)O)](2-) (103 ps). The Gd-TTDA-NP-BN shows remarkable high relaxivity (7.12 mM(-1) s(-1)) comparing to that of [Gd(TTDA-NP)(H(2)O)](2-). The fluorescence studies showed that the Gd-TTDA-NP-BN could efficiently enter PC-3 cells. Additionally, the human cancer cells xenografts using Gd-TTDA-NP-BN-Cy5.5 as an optical imaging probe clearly visualized subcutaneous PC-3 tumor and demonstrated its targeting ability to the gastrin releasing peptide (GRP) receptor overexpression. Furthermore, the biodistribution studies demonstrated significantly high tumor uptake (25.97 +/- 1.07% ID/g) and high tumor-to-normal tissue ratios at one hour post-injection of Gd-TTDA-NP-BN-Cy5.5 in the animal model. These results suggest that the Gd-1TDA-NP-BN-Cy5.5 is a superior probe for in vivo optical imaging. Importantly, the MR imaging studies showed notable signal enhancement (44.9 +/- 4.2%) on the tumor, indicating a high level accumulation of the contrast agent within the PC-3 tumor sites. Hence, targeting of prostate cancer cells was observed under in vitro and in vivo MR imaging studies using Gd-TTDA-NP-BN contrast agent. We conclude that Gd-TTDA-NP-BN and Gd-TTDA-NP-BN-Cy5.5 can be potentially used as the contrast agents for targeting GRP receptor oyerexpressing cells and tumors. (C) 2010 Elsevier Ltd. All rights reserved.