Intratumoral 18F-FLT infusion in metabolic targeted radiotherapy

Thititip Tippayamontri,Benoit Paquette,Léon Sanche,Jacques Rousseau,Roger Lecomte,René Ouellet,Otman Sarrhini,Brigitte Guérin

doi:10.1186/s13550-019-0496-7

Thititip Tippayamontri, Benoit Paquette + Show 6 more

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https://doi.org/10.1186/s13550-019-0496-7

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Abstract

BackgroundThe 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.ResultsWe 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.ConclusionConsidering 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.

Highlights

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
Considering that the therapeutic properties of 18F-FLT may be dependent on the mode of administration, we explore the biodistribution by Positron emission tomography (PET) and TRT of 18F-FLT in mice, after direct infusion of the radioactive compound in a primary tumor by convection-enhanced delivery (CED) [20]. 18F-FLT was administered directly into one tumor, while contralateral tumors simulated distant metastases
Comparison of the two sets of figures clearly shows that while primary tumor uptakes are similar for both tracers, uptakes in healthy organs are significantly reduced by i.t. administration of 18F-FLT

Summary

Introduction

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. 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. The tumor uptake and kinetics of 18F-FLT were determined and compared to 2-deoxy-2-[18F]-fluoro-Dglucose (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). Preclinical and clinical studies have demonstrated a considerable interest in 18F-FLT as a PET tracer in breast, lung, and brain cancer imaging [4, 7, 10,11,12]. 18F-FLT PET has been previously shown to provide valuable information for response assessment of tumor therapies [3, 7], and it has found limited use for tumor therapy follow-up in clinical trials [8, 13]. The only limitation remains the detection and measurement of bone tumors and metastases, due to the high 18F-FLT uptake in healthy bone marrow

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