Theranostic Approach Using Radioiodinated Trimethoprim Targeting E. coli Dihydrofolate Reductase in Engineered Cells

Area of Science:

• Oncology
• Radiopharmaceutical Therapy
• Molecular Imaging

Background:

• Radiopharmaceutical therapy (RPT) is effective for treating neuroendocrine tumors and prostate cancer.
• Synthetic RPT using engineered protein expression in tumors is a promising area, despite challenges with natural uptake.
• Advances in gene and cell therapies warrant re-exploration of synthetic RPT, especially when combined with PET imaging.

Purpose of the Study:

• To develop and evaluate a novel β-emitter radiotherapeutic probe, radioiodinated trimethoprim ([131I]I-TMP), for targeted cancer therapy.
• To develop [124/125I]I-TMP radiotracers for in vitro and in vivo uptake and imaging studies.
• To assess the therapeutic potential of a synthetic RPT approach using engineered dihydrofolate reductase expression in murine cancer models.

Main Methods:

• Development of radioiodinated trimethoprim ([131I]I-TMP) as a β-emitter radiotherapeutic probe.
• Synthesis of [124/125I]I-TMP radiotracers for uptake, imaging, and biodistribution studies.
• Evaluation of selective cytotoxicity in E. coli dihydrofolate reductase (eDHFR)-expressing cells and in vivo tumor models using PET/CT imaging.

Main Results:

• Radioiodinated trimethoprim ([131/125/124I]I-TMP) demonstrated selective uptake in eDHFR-positive tumors both in vitro and in vivo.
• Small-animal PET/CT imaging with [124I]I-TMP showed specific retention in eDHFR-expressing tumors with minimal background.
• Targeted treatment with [131I]I-TMP significantly reduced tumor volume in eDHFR-expressing tumors compared to controls.

Conclusions:

• The synthetic RPT approach using radioiodinated trimethoprim is a promising strategy for targeted cancer therapy.
• This method holds potential for theranostic applications, integrating companion imaging and radiotherapy.
• The trimethoprim-based system offers a novel platform for genetic medicine and cancer treatment.