Intratumoral (18)F-FLT infusion in metabolic targeted radiotherapy

BACKGROUND: The goal of targeted radiotherapy (TRT) is to administer radionuclides to tumor cells, while limiting radiation exposure to normal tissues. 3′-Deoxy-3′-[(18)F]-fluorothymidine ((18)F-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 (18)F-FLT alone or in combination with 5-fluorouracil (5FU), which acts as a chemotherapeutic agent and radiosensitizer. Treatment efficiency of (18)F-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 (18)F-FLT were determined and compared to 2-deoxy-2-[(18)F]-fluoro-D-glucose ((18)F-FDG) by dynamic positron emission tomography (PET) imaging following i.t. injection. The therapeutic responses of (18)F-FLT alone and with 5FU were evaluated and compared with (18)F-FDG and external beam radiotherapy (EBRT). The level of prostaglandin E(2) (PGE(2)) 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 (18)F-FLT, and compared to EBRT. RESULTS: We found that i.t. administration of (18)F-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 PGE(2) production in peritumoral tissues, no significant increase of PGE(2) was measured in this area following i.t. administration of (18)F-FLT. CONCLUSION: Considering the biochemical stability of (18)F-FLT and the physical properties of localized (18)F, this study shows that TRT via intratumoral infusion of (18)F-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 (18)F-FDG or conventional EBRT. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s13550-019-0496-7) contains supplementary material, which is available to authorized users.