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. 2012 Aug 15;23(8):1548-56.
doi: 10.1021/bc300009t. Epub 2012 Aug 1.

Synthesis and evaluation of a peptide targeted small molecular Gd-DOTA monoamide conjugate for MR molecular imaging of prostate cancer

Xueming Wu  1 , Susan M Burden-Gulley, Guan-Ping Yu, Mingqian Tan, Daniel Lindner, Susann M Brady-Kalnay, Zheng-Rong Lu
Affiliations

Synthesis and evaluation of a peptide targeted small molecular Gd-DOTA monoamide conjugate for MR molecular imaging of prostate cancer

Xueming Wu et al. Bioconjug Chem. .

Abstract

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.

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Figures

Figure 1
Figure 1
MALDI-TOF mass spectra of CLT1-dL-(Gd-DOTA)4 (A) and sCLT1-dL-(Gd-DOTA)4 (B)
Figure 2
Figure 2
Plots of 1/T1 (R1) and 1/T2 (R2) versus the concentration of the contrast agents CLT1-dL-(Gd-DOTA)4 and sCLT1-dL-(Gd-DOTA)4.
Figure 3
Figure 3
Tumor binding of CLT1-TR (A) and sCLT1-TR (B) in athymic nude mice bearing orthotopic PC3-GFP prostate tumor 2 hours after intravenous injection at a dose of 10 nmol/mouse. CLT1-TR resulted in 5.7 times higher red fluorescence intensity in the tumor than sCLT1-TR (C, n = 3, * p < 0.05). 1. tumor; 2. brain; 3. spleen; 4. liver; 5. muscle; 6. lung; 7. heart.
Figure 4
Figure 4
Histological analysis of tumor tissue injected with CLT1-TR or sCLT1-TR at a dose of 10 nmol/mouse.
Figure 5
Figure 5
Representative T1-weighted axial 2D gradient images of orthotopic PC-3 human prostate tumor before and after intravenous injection of CLT1-dL-(Gd-DOTA)4 (A) and sCLT1-dL-(Gd-DOTA)4 (B) at 0.03 mmol Gd/kg in nu/nu mice. Tumor labeled with red circle and bladder labeled with green circle.
Figure 6
Figure 6
Contrast enhancement (ΔSNR) in the tumor (A) and kidneys (B) produced by CLT1-dL-(Gd-DOTA)4 and sCLT1-dL-(Gd-DOTA)4 at 0.03 mmol-Gd/kg in nu/nu nude with athymic mice (n=6) bearing orthotopic human prostate tumor. * p < 0.05.
Figure 7
Figure 7
Biodistribution of gadolinium in the major organs and tissues of mice at 48 h after intravenous injection of CLT1-dL-(Gd-DOTA)4 and sCLT1-dL-(Gd-DOTA)4 at a dose of 0.03 mmol-Gd/kg in nu/nu athymic mice (n=4) bearing orthotopic human prostate tumor (* p < 0.05).
Scheme 1
Scheme 1
Synthesis of CLT1-dL-(Gd-DOTA)4.
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