A major challenge of spatio-temporal radiation biomedicine concerns the understanding of biophysical events triggered by an initial energy deposition inside confined ionization tracks. This contribution deals with an interdisciplinary approach that concerns cutting-edge advances in real-time radiation events, considering the potentialities of innovating strategies based on ultrafast laser science, from femtosecond photon sources to advanced techniques of ultrafast TW laser-plasma accelerator. Recent advances of powerful TW laser sources (~1019 W cm-2) and laser-plasma interactions providing ultra-short relativistic particle beams in the energy domain 5-200 MeV open promising opportunities for the development of high energy radiation femtochemistry (HERF) in the prethermal regime of secondary low-energy electrons and for the real-time imaging of radiation-induced biomolecular alterations at the nanoscopic scale. New developments would permit to correlate early radiation events triggered by ultrashort radiation sources with a molecular approach of Relative Biological Effectiveness (RBE). These emerging research developments are crucial to understand simultaneously, at the sub-picosecond and nanometric scales, the early consequences of ultra-short-pulsed radiation on biomolecular environments or integrated biological entities. This innovating approach would be applied to biomedical relevant concepts such as the emerging domain of real-time nanodosimetry for targeted pro-drug activation and pulsed radio-chimiotherapy of cancers.
During cancer radiotherapy protocols, the early profile of energy deposition is decisive for the prediction and control of radiation-induced biomolecular and sub-cellular damage. A major challenge of spatio-temporal radiation biomedicine, a newly emerging interdisciplinary domain, concerns the complete understanding of biophysical events triggered by an initial energy deposition inside confined ionization clusters (tracks) and evolving over several orders of magnitude, typically from femtosecond (1 fs = 10-15 s) and sub-nanometer scales. The innovating advent of femtosecond laser sources providing ultra-short photon beam and relativistic electron bunches, in the eV and MeV domain respectively, open exciting opportunities for a real-time imaging of radiation-induced biomolecular alterations in nanoscopic tracks. Using a very short-lived quantum probe (2p-like excited electron) and high-time resolved laser spectroscopic methods in the near IR and the temporal window 500 – 5000 fs, we demonstrate that short-range coherent interactions between the quantum probe and a small biosensor of 20 atoms (disulfide molecule) are characterized by an effective reaction radius of 9.6 ± 0.2 angströms. For the first time, femtobioradical investigations performed with aqueous environments give correlated information on spatial and temporal biomolecular damages triggered by a very short lived quantum scalpel whose the gyration radius is around 6 angströms. This innovating approach would be applied to more complex biological architectures such as nucleosomes, healthy and tumour cells. In the framework of high-quality ultra-short penetrating radiation beams devoted to pulsed radiotherapy of cancers, this concept would foreshadow the development of real-time nanobiodosimetry combined to highly-selective targeted pro-drug activation.
The innovating advent of powerful TW laser sources (~1019 W cm-z) and laser-plasma interactions providing ultra-short
relativistic particle beams (electron, proton) in the MeV domain open exciting opportunities for the simultaneous
development of high energy radiation femtochemistry (HERF) and ultrafast radiation biomedicine. Femtolysis
experiments (Femtosecondradiolysis) of aqueous targets performed with relativistic electron bunches of 2.5-15 MeV give
new insights on transient physicochemical events that take place in the prethermal regime of confined ionization tracks.
Femtolysis studies emphasize the pre-eminence of ultra-fast quantum effects in the temporal range 10-14 - 10-11 s. The
most promising advances of HERF concern the quantification of ultrafast sub-nanometric biomolecular damages (bond
weakening and bond breaking) in the radial direction of a relativistic particle beam. Combining ultra-short relativistic
particle beams and near-infrared spectroscopic configurations, laser-plasma accelerators based high energy radiation
femtochemistry foreshadows the development of real-time radiation chemistry in the prethermal regime of nascent
ionisation clusters. These physico-chemical advances would be very useful for future developments in biochemically
relevant environments (DNA, proteins) and in more complex biological systems such as living cells. The first
investigation of single and multiple irradiation shots performed at high energy level (90 MeV) and very high dose rate,
typically 1013 Gy s-1, demonstrates that measurable assessments of immediate and reversible DNA damage can be
explored at single cell level. Ultrafast in vivo irradiations would permit the development of bio-nanodosimetry on the
time scale of molecular motions, i.e. angstrom or sub-angstrom displacements and open new perspectives in the
emerging domain of ultrafast radiation biomedicine such as pulsed radiotherapy.
The intensive developments of terawatt Ti:Sa lasers permit to extend laser-plasma interactions into the relativistic regime, providing very-short electron or proton bunches. Experimental researches developed at the interface of laser physics and radiation biology, using the combination of sub-picosecond electron beams in the energy range 2-15 MeV with femtosecond near-IR optical pulses might conjecture the real-time investigation of penetrating radiation effects. A perfect synchronization between the particle beam (pump) and optical beam at 820 nm (probe) allows subpicosecond time resolution. This emerging domain involves high-energy radiation femtochemistry (HERF) for which the early spatial energy deposition is decisive for the prediction of cellular and tissular radiation damages. With vacuum-focused intensities of 2.7 x 1019 W cm-2 and a high energy electron total charge of 2.5 nC, radiation events have been investigated in the temporal range 10-13 - 10-10s. The early radiation effects of secondary electron on biomolecular sensors may be investigated inside sub-micrometric ionisation, considering the radial direction of Gaussian electron bunches. It is shown that short range electron-biosensor interactions lower than 10 A take place in nascent track structures triggered by penetrating radiation bunches. The very high dose delivery 1013 Gy s-1 performed with laser plasma accelerator may challenge our understanding of nanodosimetry on the time scale of molecular target motions. High-quality ultrashort
penetrating radiation beams open promising opportunities for the development of spatio-temporal radiation biology, a crucial domain of cancer therapy, and would favor novating applications in nanomedicine such as highly-selective shortrange pro-drug activation.
The physio-pathological roles of sulfide biomolecules in cellular environments involves redox processes and
radical reactions that alter or protect the functional properties of enzymatic systems, proteins and nucleic acids repair.
We focus on micromolar monitoring of sulfur-centered radical anions produced by direct electron attachment, using
sulfide molecules (a thioether and a disulfide biomolecule) and two complementary spectroscopic approaches: low
energy radiation femtochemistry (1-8 eV) and high energy radiation femtochemistry (2.5-15 MeV). The early step of a
disulfide bond making RS∴SR from thiol molecules involves a very-short lived odd-electron bonded intermediate for
which an excess electron is transiently localized by a preexisting two sulfide monomers complex. The reactive center of
oxidized glutathione (cystamine), a major cytoplasmic disulfide biomolecule, is also used as sensor for the real-time IR
investigation of effective reaction radius reff in homogenous aqueous environments and interfacial water of biomimetic
systems. Femtosecond high-energy electrons beams, typically in the 2.5 - 15 MeV range, may conjecture the picosecond
observation of primary radical events in nanometric radiation spurs. The real-time investigation of sulfide and disulfide
molecules opens exciting opportunities for sensitisation of confined environments (aqueous groove of DNA, protein
pockets, sub-cellular systems) to ionizing radiation. Low and high-energy femtoradical probing foreshadow the
development of new applications in radiobiology (low dose effect at the nanometric scale) and anticancer radiotherapy
(pro-drogue activation).
With the recent advent of table-top terawatt Ti:Sa laser amplifier systems, laser plasma interactions provide high-energy, femtosecond electron bunches, which might conjecture direct observation of radiation events in media of biological interest. We report on the first femtolysis studies using such laser produced relativistic electron pulses in the 2.5-15 MeV range. A real-time observation of elementary radical events is performed on water molecules and media containing an important disulfide biomolecule. The primary yield of a reducing radical produced in clusters of excitation-ionisation events (spurs) has been determined at t~3.5 10-12 s. These data provide important information about the initial energy loss and spatial distribution of early radical events. Femtolysis studies devoted to a disulfide biomolecule is noteworthy as it is the first time that a primary ionisation event can be controlled by an ultrafast radical anion formation in the prethermal regime. This innovating domain foreshadows the development of new applications in radiobiology (microdosimetry at the nanometric scale). In the near future, electron femtolysis studies would clearly enhance the understanding of radiation-induced damages in biological confined spaces (aqueous groove of DNA and protein pockets).
The elucidation ofdetailed mechanisms ofultrafast events that occur inmolecular charge transferor reaction dynamics has been made possible by recent advances in spectroscopy techniques that use ultrashort laser pulse generation. Ultrashort laser pulses (100 femtoseconds duration 1 fs 10 ''s) allow to initiate selective photochemical processes (photoejection ofepithermal electron) and to obtain unique informations on the dynamics of primary steps ofbioradical reactions involving ultrafast electron or proton transfer. 1.
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