Development of a 111In-labeled peptide derivative targeting a chemokine receptor, CXCR4, for imaging tumors.
The chemokine receptor CXCR4 is highly expressed in tumor cells and plays an important role in tumor metastasis. The aim of this study was to develop a radiopharmaceutical for the imaging of CXCR4-expressing tumors in vivo. Based on structure-activity relationships, we designed a 14-residue peptidic CXCR4 inhibitor, Ac-TZ14011, as a precursor for radiolabeled peptides. For 111In-labeling, diethylenetriaminepentaacetic acid (DTPA) was attached to the side chain of d-Lys(8) which is distant from the residues indispensable for the antagonistic activity. In-DTPA-Ac-TZ14011 inhibited the binding of a natural ligand, stromal cell-derived factor-1alpha, to CXCR4 in a concentration-dependent manner with an IC50 of 7.9 nM (Ac-TZ14011: 1.2 nM). In biodistribution experiments, more 111In-DTPA-Ac-TZ14011 accumulated in the CXCR4-expressing tumor than in blood or muscle. Furthermore, the tumor-to-blood and tumor-to-muscle ratios were significantly reduced by coinjection of Ac-TZ14011, indicating a CXCR4-mediated accumulation in tumor. These findings suggested that 111In-DTPA-Ac-TZ14011 would be a potential agent for the imaging of CXCR4 expression in metastatic tumors in vivo.
Hanaoka
Hirofumi
H
Graduate School of Pharmaceutical Sciences, Kyoto University, Yoshida Shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan.
Mukai
Takahiro
T
Tamamura
Hirokazu
H
Mori
Tomohiko
T
Ishino
Seigo
S
Ogawa
Kazuma
K
Iida
Yasuhiko
Y
Doi
Ryuichiro
R
Fujii
Nobutaka
N
Saji
Hideo
H
D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism*; D016503:Drug Delivery Systems / Q000379:methods; D015195:Drug Design; D005260:Female; D007553:Isotope Labeling / Q000379:methods; D008657:Metabolic Clearance Rate; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000378:metabolism*; D009928:Organ Specificity; D010190:Pancreatic Neoplasms / Q000000981:diagnostic imaging* / Q000378:metabolism*; D004369:Pentetic Acid / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics; D010455:Peptides / Q000138:chemical synthesis / Q000493:pharmacokinetics; D010456:Peptides, Cyclic / Q000737:chemistry / Q000493:pharmacokinetics*; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000493:pharmacokinetics; D019707:Receptors, Chemokine / Q000378:metabolism; D014018:Tissue Distribution
C512980:111indium-DTPA-Ac-TZ14011; D014408:Biomarkers, Tumor; D009363:Neoplasm Proteins; D010455:Peptides; D010456:Peptides, Cyclic; D019275:Radiopharmaceuticals; D019707:Receptors, Chemokine; D004369:Pentetic Acid