Intratumoral ¹⁸F-FLT infusion in metabolic targeted radiotherapy

The goal of targeted radiotherapy (TRT) is to administer radionuclides to tumor cells, while limiting radiation exposure to normal tissues. 3'-Deoxy-3'-[¹⁸F]-fluorothymidine (¹⁸F-FLT) is able to target tumor cells and emits a positron with energy appropriate for local (~ 1 mm range) radiotherapy. In the present work, we investigated the potential of TRT with a local administration of ¹⁸F-FLT alone or in combination with 5-fluorouracil (5FU), which acts as a chemotherapeutic agent and radiosensitizer. Treatment efficiency of ¹⁸F-FLT combined or not with 5FU was evaluated by intratumoral (i.t.) infusion into subcutaneous HCT116 colorectal tumors implanted in nu/nu mice. The tumor uptake and kinetics of ¹⁸F-FLT were determined and compared to 2-deoxy-2-[¹⁸F]-fluoro-D-glucose (¹⁸F-FDG) by dynamic positron emission tomography (PET) imaging following i.t. injection. The therapeutic responses of ¹⁸F-FLT alone and with 5FU were evaluated and compared with ¹⁸F-FDG and external beam radiotherapy (EBRT). The level of prostaglandin E₂ (PGE₂) biosynthesis was measured by liquid chromatography/tandem mass spectrometry (LC/MS/MS) in order to determine the level of inflammation to healthy tissues surrounding the tumor, after i.t. injection of ¹⁸F-FLT, and compared to EBRT.

We found that i.t. administration of ¹⁸F-FLT offers (1) the highest tumor-to-muscle uptake ratio not only in the injected tumor, but also in distant tumors, suggesting potential for concurrent metastases treatment and (2) a sixfold gain in radiotherapeutic efficacy in the primary tumor relative to EBRT, which can be further enhanced with concurrent i.t. administration of the radiosensitizer 5FU. While EBRT stimulated PGE₂ production in peritumoral tissues, no significant increase of PGE₂ was measured in this area following i.t. administration of ¹⁸F-FLT.

Considering the biochemical stability of ¹⁸F-FLT and the physical properties of localized ¹⁸F, this study shows that TRT via intratumoral infusion of ¹⁸F-FLT and 5FU could provide a new effective treatment option for solid tumors. Using this approach in a colorectal tumor model, the tumor and its metastases could be efficiently irradiated locally with much lower doses absorbed by healthy tissues than with i.t. administration of ¹⁸F-FDG or conventional EBRT.