Abstract
C-X-C chemokine receptor 4 (CXCR4) is over-expressed in multiple human cancers and correlates with tumor aggressiveness, poor prognosis and increased risk for distant metastases. Imaging agents for CXCR4 are thus highly desirable. We developed a novel CXCR4-targeted near-infrared (NIR) fluorescent probe (Peptide R-NIR750) conjugating the new developed CXCR4 peptidic antagonist Peptide R with the NIR fluorescent dye VivoTag-S750. Specific CXCR4 binding was obtained in cells overexpressing human CXCR4 (B16-hCXCR4 and human melanoma cells PES43), but not in CXCR4 low expressing cells (FB-1). Ex vivo evaluation demonstrated that PepR-NIR750 specifically detects B16-hCXCR4-derived subcutaneous tumors and lung metastases. Fluorescence Molecular Tomography (FMT) in vivo imaging was performed on mice carrying subcutaneous CHO and CHO-CXCR4 tumors. PepR-NIR750 accumulates only in CXCR4-positive expressing subcutaneous tumors. Additionally, an intense NIR fluorescence signal was detected in PES43-derived lung metastases of nude mice injected with PepR-NIR750 versus mice injected with VivoTag-S750. With a therapeutic intent, mice bearing PES43-derived lung metastases were treated with Peptide R. A the dramatic reduction in PES43-derived lung metastases was detected through a decrease of the PepR-NIR750 signal. PepR-NIR750 is a specific probe for non-invasive detection of human high CXCR4-expressing tumors and metastatic lesion and thus a valuable tool for cancer molecular imaging.
Highlights
Current imaging methods for early cancer detection are limited by low specificity and sensitivity[1]
The ability of PepR-NIR750 to bind CXCR4 was evaluated on cancer cell lines differentially expressing the receptor: FB1, human anaplastic thyroid cancer cells, known to express low level of CXCR4; CHO, Chinese hamster ovarian cells and CHO cells transfected with human CXCR4; PES43, human melanoma cell line and B16 mouse melanoma cell lines transfected with human CXCR4 (B16-CXCR4) (Figure S1)[17, 18]
To evaluate PepR-NIR750 capacity to bind CXCR4 expressing cells in vivo, FB-1 cells and B16-CXCR4 cells were s.c. inoculated in CD-1 nu/nu athymic mice
Summary
Current imaging methods for early cancer detection are limited by low specificity and sensitivity[1]. CXCL12 can attract CXCR4-positive immune cells or fibroblasts to the tumor sites to assist in tumor development. High CXCL12 in tumors attract CXCR4-positive inflammatory, vascular and stromal cells that support tumor by secreting growth factors, cytokines, chemokines and pro-angiogenic factors[9]. We reported that CXCR4 and CD133 expression identified a discrete population with stem cell properties in human ovarian cancer cells that might be critical for tumor development and chemo-resistance[14]. Early detection of CXCR4 positive cancer cells may identify and target an aggressive cellular cancer component[15]. With the intent to develop a CXCR4-targeted NIR fluorescent imaging agent Peptide R was labelled with Vivo Tag-S 750 dye (Peptide R-NIR750). Peptide R was developed as anti-metastatic agents and its potential of theranostic agent in cancer was demonstrated
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