Synthesis and evaluation of a peptide targeted small molecular Gd-DOTA monoamide conjugate for MR molecular imaging of prostate cancer.
Tumor extracellular matrix has an abundance of cancer related proteins that can be used as biomarkers for cancer molecular imaging. Innovative design and development of safe and effective targeted contrast agents to these biomarkers would allow effective MR cancer molecular imaging with high spatial resolution. In this study, we synthesized a low molecular weight CLT1 peptide targeted Gd(III) chelate CLT1-dL-(Gd-DOTA)(4) specific to clotted plasma proteins in tumor stroma for cancer MR molecular imaging. CLT1-dL-(Gd-DOTA)(4) was synthesized by conjugating four Gd-DOTA monoamide chelates to a CLT1 peptide via generation 1 lysine dendrimer. The T(1) relaxivity of CLT1-dL-(Gd-DOTA)(4) was 40.4 mM(-1) s(-1) per molecule (10.1 mM(-1) s(-1) per Gd) at 37 °C and 1.5 T. Fluorescence imaging showed high binding specificity of CLT1 to orthotopic PC3 prostate tumor in mice. The contrast agent resulted in improved tumor contrast enhancement in male athymic nude mice bearing orthotopic PC3 prostate tumor xenograft at a dose of 0.03 mmol Gd/kg. The peptide targeted MRI contrast agent is promising for high-resolution MR molecular imaging of prostate tumor.
Department of Biomedical Engineering, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA.
Xueming
X
Wu
Susan M
SM
Burden-Gulley
Guan-Ping
GP
Yu
Mingqian
M
Tan
Daniel
D
Lindner
Susann M
SM
Brady-Kalnay
Zheng-Rong
ZR
Lu
D000595:Amino Acid Sequence; D000818:Animals; D045744:Cell Line, Tumor; D060326:Chemistry Techniques, Synthetic; D006571:Heterocyclic Compounds / Q000737:chemistry*; D006801:Humans; D008279:Magnetic Resonance Imaging / Q000379:methods*; D008297:Male; D051379:Mice; D057054:Molecular Imaging / Q000379:methods*; D009942:Organometallic Compounds / Q000737:chemistry*; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000378:metabolism / Q000493:pharmacokinetics; D011471:Prostatic Neoplasms / Q000175:diagnosis* / Q000378:metabolism / Q000473:pathology; D013379:Substrate Specificity
D006571:Heterocyclic Compounds; D009942:Organometallic Compounds; D010456:Peptides, Cyclic; C510872:cyclo(cysteinyl-glycyl-leucyl-isoleucyl-isoleucyl-glutaminyl-lysyl-asparaginyl-glutamyl-cysteinyl); C050823:gadolinium 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetate