A Missing Puzzle in Dissociative Electron Attachment to Biomolecules: The Detection of Radicals

Ionizing radiation releases a flood of low-energy electrons that often causes the fragmentation of the molecular species it encounters. Special attention has been paid to the electrons’ contribution to DNA damage via the dissociative electron attachment (DEA) process. Although numerous research groups worldwide have probed these processes in the past, and many significant achievements have been made, some technical challenges have hindered researchers from obtaining a complete picture of DEA. Therefore, this research perspective calls urgently for the implementation of advanced techniques to identify non-charged radicals that form from such a decomposition of gas-phase molecules. Having well-described DEA products offers a promise to benefit society by straddling the boundary between physics, chemistry, and biology, and it brings the tools of atomic and molecular physics to bear on relevant issues of radiation research and medicine.

Electron and Photon Energy Spectra Outside of 6 MV X-ray Small Radiotherapy Field Edges Produced by a Varian iX Linac

Due to the increase in the survival probability for patients treated with modern radiotherapy techniques to live enough for experimenting the late radiation effect, low dose outside the treatment volume becomes a concern. However, besides the absorbed dose, the beam quality outside the field edge should be taken into account. This work aimed at investigating the photon and electron fluence spectra outside the field edges for several small radiotherapy fields for determining the quality of the beams in order to better evaluate the secondary effect after modern radiotherapy treatments. Phase-space files of a 6 MV X-ray beam produced by a Varian iX linac for eight small fields of 0.7 × 0.7 cm2, 0.9 × 0.9 cm2, 1.8 × 1.8 cm2, 2.2 × 2.2 cm2, 2.7 × 2.7 cm2, 3.1 × 3.1 cm2, 3.6 × 3.6 cm2, and 4.5 × 4.5 cm2 and for the reference 10 × 10 cm2 field at SSD = 100 cm were generated using the BEAMnrc code. The photon and electron fluences in each field were calculated at 0.15, 1.35, and 9.85 cm water depth and several off-axis distances using FLURZnrc. The number of low-energy electrons between 1 and 10 keV at 2 cm outside the field edge increases by 60% compared to the central axis. Due to the relatively high linear energy transfer (LET) of these electrons, the results of this work should help to better evaluate the possible late effect of secondary radiation on healthy organs close to the tumor volume after radiotherapy treatment. We also observed high-energy electrons outside the field edge that are attributed to the leakage of the primary electron beam from the head of the linac. From a standpoint of radiological protection, these electrons should be taken into account when evaluating the dose delivered to the patient’s skin.

Design, Synthesis, and Cytotoxicity Assessment of [64Cu]Cu-NOTA-Terpyridine Platinum Conjugate: A Novel Chemoradiotherapeutic Agent with Flexible Linker

Maximum benefits of chemoradiation therapy with platinum-based compounds are expected if the radiation and the drug are localized simultaneously in cancer cells. To optimize this concomitant effect, we developed the novel chemoradiotherapeutic agent [64Cu]Cu-NOTA-C3-TP by conjugating, via a short flexible alkyl chain spacer (C3), a terpyridine platinum (TP) moiety to a NOTA chelator complexed with copper-64 (64Cu). The decay of 64Cu produces numerous low-energy electrons, enabling the 64Cu-conjugate to deliver radiation energy close to TP, which intercalates into G-quadruplex DNA. Accordingly, the in vitro internalization kinetic and the cytotoxic activity of [64Cu]Cu-NOTA-C3-TP and its derivatives were investigated with colorectal cancer (HCT116) and normal human fibroblast (GM05757) cells. Radiolabeling by 64Cu results in a >55,000-fold increase of cytotoxic potential relative to [NatCu]Cu-NOTA-C3-TP at 72 h post administration, indicating a large additive effect between 64Cu and the TP drug. The internalization and nucleus accumulation of [64Cu]Cu-NOTA-C3-TP in the HCT116 cells were, respectively, 3.1 and 6.0 times higher than that for GM05757 normal human fibroblasts, which is supportive of the higher efficiency of the [64Cu]Cu-NOTA-C3-TP for HCT116 cancer cells. This work presents the first proof-of-concept study showing the potential use of the [64Cu]Cu-NOTA-C3-TP conjugate as a targeted chemoradiotherapeutic agent to treat colorectal cancer.