Targeting CXCR4-CXCL12 Axis for Visualizing, Predicting, and Inhibiting Breast Cancer Metastasis with Theranostic AMD3100-Ag_2S Quantum Dot Probe

摘要

Breast cancer metastasis remains the primary cause of death and efforts to predict and reduce metastatic risk are particularly appealing. CXC chemokine receptor 4 (CXCR4) is reported as a specific metastasis due to its chemotactic homing to CXCL12. Herein, conjugation of a CXCR4 antagonist, AMD3100, to a fluorescent silver sulfide quantum dot (Ag2S) core (QD-AMD) allows accurate detection of CXCR4 expression in tumor. Particularly, the probe precisely distinguishes highly metastatic breast cancer cells from those of lower metastatic ability. Longitudinal in vivo imaging predicts at early stages that the high CXCR4 expressing orthotopic 4T1 tumor would subsequently metastasize to lungs 14 d after tumor inoculation, while no metastasis forms from the low CXCR4 expressing MCF-7 tumor. Correlative measurements find that the CXCL12 levels in lung increase with tumor progression. Perturbations of either CXCR4 on tumor cells by QD-AMD or CXCL12 in the lungs by antibody successfully inhibit cancer metastasis. Intravenous injection of QD-AMD in primary 4T1 tumor model effectively reduces lung metastasis. More importantly, due to the intrinsic photothermal effect, the metastatic spread is more thoroughly abrogated along with substantial shrinkage of primary tumor. Altogether, the probe is promising to detect, predict, and inhibit the metastatic spread of breast tumor.