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Preparation and Evaluation of 99mTc-labeled Tridentate Chelates for Pre-targeting Using Bioorthogonal Chemistry
Published on: February 4, 2017
A Step Towards Development and Bio-evaluation of a Novel Radio-ligand 99mTc-CYX-DTPA Targeting Sigma 2 Receptors
Ritika Chaudhary1,2, Shubhra Chaturvedi2, Divya Gautam2,3
1Dr. B. R. Ambedkar Center for Biomedical Research, University of Delhi, North Campus, University Enclave, Delhi, 110007, India.
Introduction:
Development of theranostics agents targeted towards particular receptors can effectively help in the management of cancer. The overexpression of the sigma-2 receptor (S2R) in tumors establishes it as a prominent biomarker for cancer cells.
Methods:
Radiotheranostics rely on the design of specific molecules having versatility in applications of diagnosis and therapy by merely changing the radioisotope. We have designed a novel radiotheranostic S2R-targeted ligand using cyclohexylpiperazine and performed docking studies to narrow down the potential efficacious ligand. The potential molecule with G-score = -7.0 kcal/mol, was then synthesized using a three steps reaction including conjugation of 2-(4- cyclohexylpiperazine-1-yl)ethyl(CYX) with DTPA chelator. Subsequently, the molecule has been radiolabelled with 99mTc using stannous chloride as a reducing agent, and a radiolabellieng efficiency of 95.0 ± 0.59% for 99mTc-CYX-DTPA. As proof of concept, the molecule has been evaluated for its binding affinity and specificity using sigma receptors isolated from the liver membrane homogenates of mice. The binding affinity was found to be Kd = 12.84 ± 0.395 nM; Bmax = 0.5258 ± 0.001 fmol/mg, indicating a high affinity for the receptors.
Results:
In addition, the molecule was also assessed for biocompatibility using haemolysis analysis and cytotoxicity on HEK cells and MDA-MB-23, wherein the molecule showed no significant cytotoxicity up to 72 h on HEK cells and 32.42% cytotoxicity on MDA-MB-231 cells.
Conclusion:
The future work will concentrate on the demonstration of in vivo targeting and sitespecific accumulation of the molecule along with its suitability for theranostics applications.
Insights
A novel theranostic agent targeting sigma-2 receptors (S2R) was developed for cancer management. This S2R-targeted ligand shows high affinity and potential for in vivo applications in cancer diagnosis and therapy.
Area of Science:
- Oncology
- Radiochemistry
- Molecular Imaging
Background:
- Theranostic agents targeting specific receptors aid cancer management.
- Sigma-2 receptor (S2R) is overexpressed in tumors, making it a key cancer biomarker.
Purpose of the Study:
- To design and synthesize a novel S2R-targeted radiotheranostic ligand.
- To evaluate the binding affinity, specificity, and biocompatibility of the developed ligand.
Main Methods:
- A novel S2R-targeted ligand (CYX-DTPA) was designed using cyclohexylpiperazine and synthesized.
- The ligand was radiolabeled with 99mTc, achieving 95.0 ± 0.59% efficiency.
- Binding affinity and specificity were assessed using mouse liver membrane homogenates.
Main Results:
- The radiolabeled ligand (99mTc-CYX-DTPA) demonstrated high binding affinity (Kd = 12.84 ± 0.395 nM) for S2R.
- Biocompatibility studies showed no significant cytotoxicity on HEK cells up to 72h.
- Moderate cytotoxicity (32.42%) was observed on MDA-MB-231 cancer cells.
Conclusions:
- The developed S2R-targeted ligand shows promise for theranostic applications.
- Future studies will focus on in vivo validation for targeting and accumulation.
- Further optimization may be needed for enhanced cancer cell targeting and therapeutic efficacy.
