title: 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 (k(ex)(298)) for [Gd(TTDA-NP)(H(2)O)](2-) (110×10(6)s(-1)) is significantly higher than that of [Gd(DTPA)(H(2)O)](2-) complex and the rotational correlation time (τ(R)) for [Gd(TTDA-NP)(H(2)O)](2-) (145ps) is also higher than those of [Gd(TTDA)(H(2)O)](2-) (104ps) and [Gd(DTPA)(H(2)O)](2-) (103ps). The Gd-TTDA-NP-BN shows remarkable high relaxivity (7.12mM(-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-TTDA-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 overexpressing cells and tumors.
authors.affiliation: Department of Biological Science and Technology, National Chiao Tung University, 75 Bo-Ai Street, Hsinchu 300, Taiwan.
authors.forename: Ying-Hsiu
authors.initials: YH
authors.lastname: Lin
authors.forename: Kasala
authors.initials: K
authors.lastname: Dayananda
authors.forename: Chiao-Yun
authors.initials: CY
authors.lastname: Chen
authors.forename: Gin-Chung
authors.initials: GC
authors.lastname: Liu
authors.forename: Tsai-Yueh
authors.initials: TY
authors.lastname: Luo
authors.forename: Hui-Sheng
authors.initials: HS
authors.lastname: Hsu
authors.forename: Yun-Ming
authors.initials: YM
authors.lastname: Wang
mesh_terms: D000818:Animals; D001839:Bombesin / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000493:pharmacokinetics; D045744:Cell Line, Tumor; D002470:Cell Survival; D003287:Contrast Media / Q000138:chemical synthesis / Q000493:pharmacokinetics; D006801:Humans; D007624:KB Cells; D049449:Luminescence; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D008856:Microscopy, Fluorescence; D009942:Organometallic Compounds / Q000138:chemical synthesis / Q000493:pharmacokinetics; D011471:Prostatic Neoplasms / Q000175:diagnosis*; D019275:Radiopharmaceuticals; D018004:Receptors, Bombesin / Q000032:analysis*; D019265:Spectroscopy, Near-Infrared
chemical_list: D003287:Contrast Media; D009942:Organometallic Compounds; D019275:Radiopharmaceuticals; D018004:Receptors, Bombesin; C496928:gadolinium 3,6,10-tri(carboxymethyl)-3,6,10-triazadodecanedioic acid; D001839:Bombesin