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Development of a 111In-labeled peptide derivative targeting a chemokine receptor, CXCR4, for imaging tumors
Hirofumi Hanaoka1, Takahiro Mukai, Hirokazu Tamamura
1Graduate School of Pharmaceutical Sciences, Kyoto University, Yoshida Shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan.
Abstract:
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.
Insights
Researchers developed a new radiopharmaceutical, 111In-DTPA-Ac-TZ14011, for imaging tumors that express the chemokine receptor CXCR4. This agent shows promising accumulation in tumors, aiding in the detection of metastatic disease.
Area of Science:
- Oncology
- Radiochemistry
- Molecular Imaging
Background:
- Chemokine receptor CXCR4 is overexpressed in tumor cells, driving tumor metastasis.
- Targeting CXCR4 is a strategy for cancer imaging and therapy.
- Developing specific radiopharmaceuticals is crucial for in vivo imaging.
Purpose of the Study:
- To design and develop a novel radiopharmaceutical for imaging CXCR4-expressing tumors.
- To evaluate the efficacy of the developed agent in preclinical models.
- To assess its potential for diagnosing metastatic cancers.
Main Methods:
- Design of a 14-residue peptidic CXCR4 inhibitor (Ac-TZ14011) based on structure-activity relationships.
- Conjugation of diethylenetriaminepentaacetic acid (DTPA) for Indium-111 (111In) labeling.
- In vitro assessment of binding inhibition to CXCR4.
- In vivo biodistribution studies in tumor-bearing models.
Main Results:
- The radiolabeled peptide, 111In-DTPA-Ac-TZ14011, demonstrated potent inhibition of stromal cell-derived factor-1alpha binding to CXCR4 (IC50 = 7.9 nM).
- Significant accumulation of 111In-DTPA-Ac-TZ14011 was observed in CXCR4-expressing tumors compared to blood and muscle.
- Coinjection of the unlabeled inhibitor confirmed CXCR4-mediated tumor uptake, enhancing tumor-to-tissue ratios.
Conclusions:
- 111In-DTPA-Ac-TZ14011 is a promising CXCR4-targeting radiopharmaceutical.
- The agent facilitates in vivo imaging of CXCR4 expression in tumors.
- This radiotracer holds potential for diagnosing and monitoring metastatic cancers.
