Abstract
Sphingosine-1-phosphate (S1P) is a phospholipid that regulates pleiotropic biological activities and exerts extracellular functions by binding to five specific G-protein-coupled receptors, S1P receptors (S1PR) 1–5. When activated by S1P, S1PR promote the proliferation and invasion of tumor cells by inducing the formation of new blood vessels. We developed and assessed a new monoclonal antibody imaging probe 99mTc-HYNIC-S1PR1mAb, to explore the feasibility of targeting the S1PR1 in vitro and in vivo. S1PR1mAb was prepared and followed by technetium-99m labeling with succinimidyl 6-hydraziniumnicotinate hydrochloride. Cell uptake and blocking studies were performed to investigate the binding specificity of 99mTc-HYNIC-S1PR1mAb in vitro. 99mTc-HYNIC-S1P1mAb was also tested in vivo in mice xenografted with SK-HEP-1 (high-expression of S1PR1) and MCF-7 (low-expression of S1PR1) using single-photon emission-computed tomography (SPECT). Ex vivo gamma counting of tissues from tumor-bearing mice was used to evaluate 99mTc-HYNIC-S1PR1mAb biodistribution. The biodistribution study results showed significantly higher uptake in SK-HEP-1 tumors than in MCF-7 tumors (P < 0.001). Reduced uptake of 99mTc-HYNIC-S1PR1mAb in SK-HEP-1 was observed in tumor-bearing nude mice pretreated with fingolimod, which binds competitively to the receptors, especially S1PR1. 99mTc-HYNIC-S1PR1mAb can be synthesized and specifically targeted to S1PR1 in vitro and in vivo, allowing S1PR1 expression assessment with SPECT imaging.
Highlights
Sphingosine-1 phosphate (S1P) is a bioactive sphingolipid metabolite that plays an important role in the maturation and homeostasis of the vascular system and in the transport of immune cells [1]
Western blotting was used to analyze the expression of S1PR1 in SK-HEP-1 and MCF-7 cells
The results demonstrated that SKHEP-1 cells overexpressed S1PR1, while MCF-7 cells rarely expressed S1PR1 (Figure 1A and Supplementary Figures 2–4)
Summary
Sphingosine-1 phosphate (S1P) is a bioactive sphingolipid metabolite that plays an important role in the maturation and homeostasis of the vascular system and in the transport of immune cells [1]. S1P can bind to specific G protein-coupled receptors on the cell membrane surface to generate downstream signals that regulate physiological processes. Studies have shown that S1PR1 is highly expressed in colorectal cancer and that the up-regulation of S1PR1 expression is closely related to deep infiltration of cancer cells and liver metastasis. S1PR1 stimulates bladder cancer cells to secrete transforming growth factor (TGF)-b and IL-6, thereby inducing the aggregation of regulatory T-cells (Tregs) [10]. These studies demonstrate that S1PR1 is a promising cancer biomarker that may play a role in the prognosis of certain tumors
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