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Indium-111-labeled CD166-targeted peptide as a potential nuclear imaging agent for detecting colorectal cancer stemlike cells in a xenograft mouse model

2020.02.24.

Siao-Syun Guan et al., EJNMMI Research, 2020

Summary

Colorectal cancer (CRC) is the third most frequent occurring cancer in men and the second most frequent occurring cancer in women, with nearly 1.65 million new diagnosed cases and about 832,000 deaths in 2015. One possible cause of treatment failure is that the tumor site contains a small population of tumor-initiating cells termed cancer stem cells (CSCs). CSCs are involved in drug resistance, metastasis, and relapse of cancers, which can significantly affect tumor therapy. Hence, to develop specifically therapeutic target probe at CSCs for improvement of survival and quality of life of cancer patients is urgently needed. The CD166 protein has been suggested to be involved in CRC tumorigenesis and to be considered a marker for colorectal CSCs (CRCSCs) detection. In this study, therefore, the authors attend to apply a nuclear imaging agent probe, Glycine18-Cystine-linked CD166-targeted peptides (CD166tp-G18C), to detect the changes of CD166 level in a CRC xenograft mouse model.

Results from the NanoSPECT/CT

For the animal experiment, the authors have used a nanoSPECT/CT, which provided a good enough sensitivity and resolution to make the tumor uptake visible after 2 hours p.i., and see significant differences in the uptake of the  applied tracers.
To create a xenograft tumor model, male BALB/c nude mice were subcutaneously inoculating CD166+HCT15 cells (1 × 106 cells) for 2 weeks, and then the 111In-DTPA, 111In-DTPA-G18C, 111In-DTPA-CD166tp-C, and 111In-DTPA-CD166tp-G18C (740 MBq/kg/mouse) were intravenously injected into mice. The imaging of CD166 in mice at 2, 4, 24, and 48 h were detected by the nanoSPECT/CT. For competitive study, the CD166+HCT15-derived xenograft mice were pre-treated with CD166tp-G18C (0, 10, and 50 mg/kg) for 6 h. Every mouse then received 740 MBq/kg 111In-DTPA-CD166tp-G18C via intravenous injection for 24 and 48 h. The competitive CD166 images were observed with the same procedure.

Figure 8. shows the main results from the SPECT/CT acquisitions: The nuclear imaging tracer of 111In-DTPA-CD166tp-G18C for detection of CD166-positive colorectal tumor in vivo. a) The colorectal tumor nuclear imaging analysis in CD166+HCT15 xenograft mice. The 111In-DTPA-CD166tp-G18C and control groups (740 MBq/kg/per mouse) were intravenously injected into mice for 2, 4, 24, and 48 h and detected by a nanoSPECT/CT. Group I, 111In-DTPA; Group II, 111In-DTPA-G18C; Group III, 111In-DTPA-CD166tp-C; Group IV, 111In-DTPA-CD166tp-G18C. b) Quantification of nuclear images in tumor areas of colorectal tumor xenograft mice. The circled positions in images were quantified by a 3D analysis software. Data are presented as mean ± SD (n ≥ 3). *P < 0.05, versus control group. c) The competitive study of 111In-DTPA-CD166tp-G18C in CD166+HCT15 xenograft mice. After tumor xenograft mice were intravenously injected with CD166tp-G18C (0, 10, and 50 mg/kg) for 6 h, 111In-DTPA-CD166tp-G18C (740 MBq/kg/mouse) was intravenously injected into mice for 24 and 48 h and detected by a nanoSPECT/CT. d) Quantification of nuclear images in tumor areas of colorectal tumor xenograft mice. Data are presented as mean ± SD (n ≥ 3). *P < 0.05, versus 0 mg/kg CD166tp-G18C group, #P < 0.05, versus 0 mg/kg CD166tp-G18C group.

  • The authors have developed a nuclear imaging agent (111In-DTPA-CD166tp-G18C) using CD166tp-G18C as a probe for CD166-positive CRCs detection in a xenograft mouse model. In this xenograft model, when the tumor size achieved about 150 mm3 which possessed about 1 × 107 CD166-postive cells (cancer cell average diameter: 15 μm), the nanoSPECT/CT detection started to perform.
  • These results suggest that CD166-positive CRC exhibited characteristics of CSCs, so it may be a useful drug screening tool for CRC diagnosis. The authors synthesized DTPA-CD166tp-G18C and radiolabeled with Indium-111 for detecting CD166 imaging by using nanoSPECT/CT in CD166-positive CRC xenograft mice. The bio-distribution of 111In-DTPA-CD166tp-G18C confirmed the accumulation of CD166-positive cells in tumors. Therefore, 111In-DTPA-CD166tp-G18C may be a potential nuclear imaging agent for diagnosis of CRCSCs. The CD166 bound peptide-based nuclear imaging may provide physicians to classify cancer cells before treatment and monitor patients with a history of CRC after surgery or drug treatment.

Full article on EJNMMI Research

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