Novel TSPO-targeted Doxorubicin Prodrug for Colorectal Carcinoma Cells

  • Anticancer Res. 2020 Oct;40(10):5371-5378. doi: 10.21873/anticanres.14545.
Jemianne B Jia  1  2 ,  Xiaoxi Ling  3 ,  Minzhi Xing  1  4 ,  Johannes M Ludwig  1  4 ,  Mingfeng Bai  5  6  7 ,  Hyun S Kim  8  4  7  9  10
Affiliations
  • 1. Interventional Oncology Translational Laboratory, University of Pittsburgh School of Medicine, Pittsburgh, PA, U.S.A.
  • 2. Department of Radiology, Kaiser Permanente Los Angeles Medical Center, Los Angeles, CA, U.S.A.
  • 3. Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, U.S.A.
  • 4. Section of Interventional Radiology, Department of Radiology and Biomedical Imaging, Yale School of Medicine, New Haven, CT, U.S.A.
  • 5. Department of Radiology, University of Pittsburgh School of Medicine, Pittsburgh, PA, U.S.A. [email protected] [email protected].
  • 6. Department of Bioengineering, University of Pittsburgh School of Medicine, Pittsburgh, PA, U.S.A.
  • 7. University of Pittsburgh Cancer Institute, Pittsburgh, PA, U.S.A.
  • 8. Interventional Oncology Translational Laboratory, University of Pittsburgh School of Medicine, Pittsburgh, PA, U.S.A. [email protected] [email protected].
  • 9. Section of Medical Oncology, Department of Medicine, Yale School of Medicine, New Haven, CT, U.S.A.
  • 10. Yale Cancer Center, Yale University, New Haven, CT, U.S.A.
PMID: 32988856 DOI: 10.21873/anticanres.14545
Abstract

Background/aim: 18 kDa Translocator protein (TSPO) is a mitochondrial protein up-regulated in colorectal carcinoma (CRC). Our purpose was to develop a TSPO-targeted doxorubicin prodrug (Dox-TSPO) which can be loaded onto drug-eluting beads for transarterial chemoembolization. Furthermore, we evaluated its loading and release kinetics and effects on cell viability.

Materials and methods: N-Fmoc-DOX-14-O-hemiglutarate was coupled with a TSPO ligand, 6-TSPOmbb732, using classical N,N,N',N'-tetramethyl-O-(1H-benzotriazol-1-yl)uranium hexafluorophosphate coupling to produce Dox-TSPO. Loading and elution studies were performed using DC beads™. Cell viability studies were performed using CellTiter-Glo® Luminescent Cell Viability Assay.

Results: Dox-TSPO was successfully synthesized and readily loaded onto and eluted from DC beads™, albeit at a slower rate than free doxorubicin. CRC cell lines expressing TSPO were 2- to 4- fold more sensitive to Dox-TSPO compared to free doxorubicin at 72 h.

Conclusion: Dox-TSPO is a promising candidate for targeted and directed Cancer treatment of CRC liver metastases.

Keywords
TSPO; Targeted therapy; colorectal carcinoma; doxorubicin; prodrug.
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