RGD targeted poly(L-glutamic acid)-cystamine-(Gd-DO3A) conjugate for detecting angiogenesis biomarker alpha(v) beta3 integrin with MRT, mapping.
Cyclic Arg-Gly-Asp-D-Phe-Lys [c(RGDfK)] targeted poly(L-glutamic acid) (PGA)-(Gd-DO3A) conjugate with a biodegradable cystamine spacer was prepared and evaluated for in vivo detection of an angiogenesis biomarker, alpha(v)beta3 integrin, in neoplastic tissues with T1 mapping, a quantitative magnetic resonance imaging (MRI) technique. The binding activity of the c(RGDfK) containing conjugate was investigated using in vitro vitronectin assay with human prostate carcinoma DU145 cell line and Kaposi's sarcoma SLK cell line. The peptide c(RGDfK) and PGA-cystamine-(Gd-DO3A) conjugate were used as controls. The binding affinity of polymer bound c(RGDfK) was slightly lower than free c(RGDfK) peptide. The RGD targeted conjugate had higher binding affinity to the DU145 cells than the SLK cells, which was consistent to free c(RGDfK). The imaging of alpha(v)beta3 integrin with targeted PGA-cystamine-(Gd-DO3A) was evaluated in nude mice bearing DU145 and SLK xenografts at a dose of 5 micromol-Gd/kg. The targeted conjugate demonstrated higher in vivo binding affinity to the DU145 xenografts than the SLK xenografts, resulting in a significant decrease of T1 values of water protons in the periphery of the DU145 tumors as shown in the MR T1 maps. No significant decrease of T1 values was observed in the SLK tumor with the targeted conjugate and in both tumors with the non-targeted conjugate. The targeted polymeric Gd(III) chelate conjugate with a degradable spacer has the potential to be a new paradigm for safe and effective probes in molecular imaging with quantitative MR T1 mapping.
Ke
Tianyi
T
Department of Pharmaceutics and Pharmaceutical Chemistry; , University of Utah, Salt Lake City, UT 84108, USA.
Jeong
Eun-Kee
EK
Wang
Xuli
X
Feng
Yi
Y
Parker
Dennis L
DL
Lu
Zheng-Rong
ZR
D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002460:Cell Line; D003287:Contrast Media; D003538:Cystamine / Q000737:chemistry; D016503:Drug Delivery Systems / Q000379:methods; D006801:Humans; D007089:Image Enhancement / Q000379:methods*; D039302:Integrin alphaVbeta3 / Q000378:metabolism*; D008279:Magnetic Resonance Imaging / Q000379:methods*; D009389:Neovascularization, Pathologic / Q000175:diagnosis* / Q000378:metabolism*; D009842:Oligopeptides / Q000737:chemistry; D009942:Organometallic Compounds; D011099:Polyglutamic Acid / Q000737:chemistry
D015415:Biomarkers; D003287:Contrast Media; D039302:Integrin alphaVbeta3; D009842:Oligopeptides; D009942:Organometallic Compounds; C090600:gadobutrol; D011099:Polyglutamic Acid; C047981:arginyl-glycyl-aspartic acid; D003538:Cystamine