RT Journal Article
SR Electronic
T1 A Peptide Heterodimer Tracer Targeting CXCR4 and Integrin α<sub>v</sub>β<sub>3</sub> for Pancreatic Cancer Imaging
JF Journal of Nuclear Medicine
JO J Nucl Med
FD Society of Nuclear Medicine
SP 1498
OP 1498
VO 62
IS supplement 1
A1 Yaqun Jiang
A1 Yu Long
A1 Yongxue Zhang
A1 Xiaoli Lan
A1 Yongkang Gai
YR 2021
UL http://jnm.snmjournals.org/content/62/supplement_1/1498.abstract
AB 1498Objectives: Nowadays, pancreatic cancer is a formidable disease to diagnose. The CXC chemokine receptor 4 (CXCR4) and integrin αvβ3 play an important role in tumor development, progression, invasion and metastasis, which are overexpressed in many types of human cancers. Studies have indicated that probes which can recognize multiple targets could achieve higher targeting efficiency than their corresponding monospecific counterparts. Therefore, in this study, we synthesized a heterodimeric tracer 68Ga-yG5-RGD targeting both CXCR4 and integrin αvβ3 and evaluated its feasibility and utility in PET imaging of pancreatic cancer. Methods: yG5 peptide, an analogy of peptide FC131, was first modified with bifunctional chelator NO2AtBu-N3 and then conjugated to BCN-PEG4-c(RGDyK) via copper free click chemistry. The resulting precursor was identified and then radiolabeled with 68Ga. The in vitro and in vivo stability was confirmed by radio-HPLC. The expression levels of CXCR4 and integrin αvβ3 of BXPC3 (human pancreatic cancer cell) and MX-1 (human breast cancer cell) cells and their corresponding tumor tissues were characterized by western blot and immunohistochemical analysis. The in vitro cell studies were performed. PET/CT scan and biodistrbution studies of 68Ga-yG5-RGD, 68Ga-yG5 and 68Ga-RGD were performed using BXPC3 xenograft tumor mice. As negative control, the in vivo performance of 68Ga-yG5-RGD was also evaluated in MX-1 tumor-bearing mice. Results: yG5 and yG5-RGD were successfully synthesized and labeled with 68Ga with high yield (&gt; 99%) and purity (&gt; 99%) at molar activity of 74~92 MBq/nmol (n = 6). Less than 1% disassociation was observed after incubation in PBS and fresh human serum at 37 ℃ for 2 h in vitro. 68Ga-yG5-RGD also showed high in vivo metabolic stability. BXPC3 showed moderate expression level of CXCR4 as well as integrin αvβ3, while MX-1 low or not. The uptake of 68Ga-yG5-RGD was higher than 68Ga-yG5 (P &lt; 0.001) and 68Ga-RGD (P &lt; 0.001) and could be blocked by excess amounts of AMD3100 (FDA-approved CXCR4 antagonist) or unlabeled RGD (P &lt; 0.001). On small animal PET/CT images, 68Ga-yG5-RGD was mainly excreted via liver and kidney. BXPC3 tumor was visualized more clearly post injection of 68Ga-yG5-RGD than that of 68Ga-yG5 and 68Ga-RGD within observation time. What’s more, BXPC3 tumors were still clearly visible at 2 h post injection of 68Ga-yG5-RGD. In addition, in vivo blocking studies showed that the tumor visualization could be blocked at 30 min post co-injection of 68Ga-yG5-RGD and block agents. As control, no elevated uptake of 68Ga-yG5-RGD was found in MX-1 tumors. The biodistribution results were consistent with imaging. Conclusions: In this study, a peptide-based heterodimeric tracer 68Ga-yG5-RGD was successfully developed with excellent in vitro and in vivo performance. The dual-receptor targeting strategy achieves improved tumor-targeting efficiency and prolonged tumor retention in BXPC3 tumor, making 68Ga-yG5-RGD a promising tracer for noninvasive detection of tumors which express either CXCR4 or integrin αvβ3 or both, showing promising clinical translation prospects. Acknowledgements: This work was supported by the National Natural Science Foundation of China (No. 81801738, 81630049 and 81771863).