Related Experiment Video
Updated: Oct 21, 2026
Computed Tomography-guided Time-domain Diffuse Fluorescence Tomography in Small Animals for Localization of Cancer Biomarkers
Published on: July 17, 2012
Sodium Multivitamin Transporter-Targeted Fluorochrome Facilitates Enhanced Metabolic Evaluation of Tumors Through
Feredun Azari1,2,3, Gregory T Kennedy4,5, Ashley Chang4,5
1Department of Thoracic Surgery, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA. feredun.azari@pennmedicine.upenn.edu.
Background:
Intraoperative molecular imaging (IMI)-guided resections have been shown to improve oncologic outcomes for patients undergoing surgery for solid malignancies. The technology utilizes fluorescent tracers targeting cancer cells without the use of any ionizing radiation. However, currently available targeted IMI tracers are effective only for tumors with a highly specific receptor expression profile, and there is an unmet need for IMI tracers to label a broader range of tumor types. Here, we describe the development and testing of a novel tracer (CR)-S0456) targeted to the sodium multivitamin transporter (SMVT).
Methods:
Preclinical models of fibrosarcoma (HT-1080), lung (A549), breast (4T1), and renal cancers (HEK-293 T) in vitro and in vivo were used for assessment of (CR)-S0456 specific tumor labeling via sodium-mediated SMVT uptake in dipotassium phosphate or choline chloride-containing media buffer. Additionally, pharmacologic inhibition of multiple intracellular coenzyme-R obligate signaling pathways, including holocarboxylase synthetase (sulconazole nitrate), PI3K/AKT/mTOR (omipalisib), and calmodulin-dependent phosphatase (calmidazolium), were investigated to assess (CR)-S0456 uptake kinetics. Human fibrosarcoma-bearing xenografts in athymic nude mice were used for tumor and metabolic-specific labeling. Novel NIR needle confocal laser endomicroscopic (nCLE) intratumoral sampling was performed to demonstrate single-cell specific labeling by CR-S0456.
Results:
CR-S0456 localization in vitro correlated with highly proliferative cell lines (MTT) and doubling time (p < 0.05) with the highest microscopic fluorescence detected in aggressive human fibrosarcomas (HT-1080). Coenzyme-R-specific localization was demonstrated to be SMVT-specific after competitive inhibition of internal localization with excess administration of pantothenic acid. Inhibiting the activity of SMVT by affecting sodium ion hemostasis prevented the complete uptake of CR-S0456. In vivo validation demonstrated (CR)-S0456 localization to xenograft models with accurate identification of primary tumors as well as margin assessment down to 1 mm3 tumor volume. Systemic treatment of xenograft-bearing mice with a dual PI3K/mTOR inhibitor suppressed intratumoral cell signaling and (CR)-S0456 uptake via a reduction in SMVT expression. Novel analysis of in vivo intratumoral cytologic fluorescence using near-infrared confocal laser endomicroscopy demonstrated the absence of coenzyme-R-mediated NIR fluorescence but not fibroblast activation protein (FAP)-conjugated fluorochrome, indicating specific intracellular inhibition of coenzyme-R obligate pathways.
Conclusion:
These findings suggest that a SMVT-targeted NIR contrast agent can be a suitable tracer for imaging a wide range of malignancies as well as evaluating metabolic response to systemic therapies, similar to PET imaging with immune checkpoint inhibitors.
Insights
A new near-infrared fluorescent tracer targeting the sodium multivitamin transporter (SMVT) shows promise for intraoperative molecular imaging of diverse solid tumors. This novel tracer aids in tumor detection and margin assessment, potentially improving surgical outcomes.
Area of Science:
- Oncology
- Molecular Imaging
- Biotechnology
Background:
- Intraoperative molecular imaging (IMI) improves oncologic outcomes for solid tumors by using fluorescent tracers without ionizing radiation.
- Current IMI tracers are limited to tumors with specific receptor expression, necessitating tracers for a broader range of cancers.
- Development of a novel tracer targeting the sodium multivitamin transporter (SMVT) is described.
Purpose of the Study:
- To develop and test a novel tracer, (CR)-S0456, targeting the sodium multivitamin transporter (SMVT) for intraoperative molecular imaging.
- To assess the tracer's efficacy in labeling various cancer types in preclinical models.
- To evaluate the tracer's potential for assessing metabolic response to systemic therapies.
Main Methods:
- Preclinical models (fibrosarcoma, lung, breast, renal cancers) were used for in vitro and in vivo assessment of (CR)-S0456 labeling via SMVT uptake.
- Pharmacologic inhibition of intracellular signaling pathways (holocarboxylase synthetase, PI3K/AKT/mTOR, calmodulin-dependent phosphatase) was investigated to assess uptake kinetics.
- Near-infrared needle confocal laser endomicroscopy (nCLE) was employed for single-cell specific labeling demonstration in human fibrosarcoma xenografts.
Main Results:
- (CR)-S0456 localization correlated with cell proliferation and was highest in aggressive fibrosarcomas, demonstrating SMVT-specific uptake.
- In vivo studies accurately identified primary tumors and assessed margins down to 1 mm³.
- Systemic PI3K/mTOR inhibition reduced SMVT expression and (CR)-S0456 uptake, indicating potential for evaluating metabolic response.
Conclusions:
- A SMVT-targeted near-infrared contrast agent is a viable tracer for imaging diverse malignancies.
- This tracer can potentially evaluate metabolic response to systemic therapies, analogous to PET imaging.
- The findings support the use of SMVT-targeted tracers to broaden the application of intraoperative molecular imaging.
