Method for determining the dose of ionizing radiation absorbed by a radiosensitive film in the form of a solid polymer exhibiting radiofluorogenic properties.

Abstract

TITLE: Method for determining the dose of ionizing radiation absorbed by a radiosensitive film in the form of a solid polymer exhibiting radiofluorogenic properties. The invention relates to a method for determining the dose of ionizing radiation absorbed by a radiosensitive film in the form of a solid polymer, characterized in that it comprises the following steps: a) providing at least one radiosensitive film in the form of a solid polymer, namely a solid polymer doped with an activator and with a radiosensitive molecule, also exhibiting radiofluorogenic properties; b) measuring the fluorescence response of said at least one film; c) irradiating said at least one film; d) measuring the fluorescence response of said at least one film thus irradiated; e) determining a change in fluorescence of said at least one film between step d) and step b), thereby ultimately determining the dose of ionizing radiation absorbed by said at least one film.

Description

Title of the invention: Method for determining a dose of ionizing radiation absorbed by a radiosensitive film in the form of a solid polymer having radiofluorogenic properties. Technical field of the invention

[0001] The present invention relates to the field of detection of ionizing radiation. It is aimed in particular at dosimetry applications in radiotherapy such as machine quality control or patient dosimetric monitoring. Applications in radiobiology or even in radiation protection are also targeted. State of the art

[0002] Film dosimetry is a widespread technique in radiotherapy that offers the possibility of obtaining a 2D dose distribution with high spatial resolution. It can be used for quality control (QC) of complex beams such as in Intensity Modulated Radiation Therapy (IMRT), stereotaxic radiotherapy or FLASH radiotherapy. It also finds applications in radiobiology.

[0003] The most widely used films are radiochromic films. There are two main families.

[0004] The first family concerns films whose active layer is made up of monomers polymerizing under the effect of ionizing radiation to form macromolecules. These macromolecules must have optical properties different from those of the initial monomer, to make it possible to trace the post-irradiation absorbed dose.

[0005] Radiochromic films named GAFchromic™ belong to this first family. The active layer is based on diacetylene crystals (monomers) which, under the effect of ionizing radiation, form polydiacethylene chains. The polymerization of the film involves a change in the absorbance of the film, before and after irradiation, which can be measured with a spectrophotometer or a densitometer. They are currently used in radiotherapy, particularly for beam quality control, or in radiobiology. Their use can also be carried out in vzvo for radiotherapy, mainly for special techniques such as total body irradiation or dose measurements directly on the skin. Indeed, these films have a sensitivity limit of around 0.01 Gy to the absorbed dose of ionizing radiation, compatible with this type of use.

[0006] The second family concerns solid polymers whose active element is a transparent radiochromic molecule (before irradiation) which under the effect of a ionizing radiation and an activator, undergoes a structural modification and a change in color. Here too, the analysis of the change in color of the film is based on a measurement of a variation in the absorbance of the film before and after irradiation. Indeed, the change in color implies a modification in the absorption spectrum dependent on the dose absorbed in the film. Typically, these films have a sensitivity limit of the order of 0.2 to 0.5 Gy. As a result, these films are difficult to use for in vivo applications in radiotherapy. However, they are widely used to create 3D phantoms for the quality control of radiotherapy treatments.

[0007] Despite lower sensitivity than GAFchromic™ type radiochromic films, solid polymer-based radiochromic films have practical advantages such as relatively easy custom shaping for all types of use, insensitivity to oxygen and lower manufacturing costs.

[0008] This has resulted in many research groups seeking to improve their sensitivity to combine the different advantages.

[0009] Improving the sensitivity (to the absorbed dose of ionizing radiation) of a solid polymer-based radiochromic film is therefore an active research topic.

[0010] The research conducted in this regard focuses on the formulation of the film. This may lie in the choice of the solid polymer. It may also lie in the choice of the radiochromic molecule present in the solid polymer, or its concentration in this polymer. It may also lie in additional doping of the solid polymer: incorporation of nanoparticles with a high atomic number (Z) (e.g. gold nanoparticles, Bi2O3 nanoparticles), incorporation of organometallic complexes based on heavy metals (e.g. bismuth neodecanoate, zinc octoate, etc.).

[0011] These searches lead to more or less satisfactory results. Summary of the invention

[0012] One objective of the invention is to improve the detection sensitivity of a radiosensitive film in the form of a solid polymer.

[0013] To this end, the invention proposes a method for determining a dose of ionizing radiation absorbed by a radiosensitive film in the form of a solid polymer, characterized in that it comprises the following steps: (a) providing at least one radiosensitive film in the form of a solid polymer, namely a solid polymer doped with an activator and with a radiosensitive molecule also having radiofluorogenic properties; b) measuring the fluorescence response of said at least one film; c) irradiating said at least one film; d) measuring the fluorescence response of said at least one film thus irradiated; e) determining a variation in fluorescence of said at least one film between step d) and step b), this finally making it possible to determine the dose of ionizing radiation absorbed by said at least one film.

[0014] The device according to the invention may comprise at least one of the following characteristics, taken alone or in combination:

[0015] - the radiosensitive molecule of the film provided in step a) also having radiochromic properties, the method then comprises the additional steps of: B) measuring, between step a) and step c), the absorbance response of said at least one film; D) measuring, after step c), the absorbance response of said at least one film; and E) determining a variation in absorbance of said at least one film between step D) and step B);

[0016] - steps B) and D) are carried out at least in the visible range and / or in the near ultraviolet;

[0017] steps b) and d) are carried out in the near infrared and / or visible and / or ultraviolet;

[0018] - the solid polymer is a polymer based on polysiloxanes, polyurethane, poly(meth)acrylates, for example polymethyl methacrylate (PMMA), polystyrenes, cyclic olefin copolymers (COCs), polyolefins, polycarbonates, epoxy resins, polyesters, polysulfones, or copolymers such as styrene-acrylonitrile or terpolymers such as acrylonitrile butadiene styrene (ABS);

[0019] - the radiosensitive molecule is chosen from at least one of the following families: diphenylmethanes and triphenylmethanes, fluorans, diazonium salts, fulgides, fulgimides, diarylethenes, dithienylethenes, polydiacetylenes, oxazine leuco-dyes, spiropyrans, spirooxazines, chromenes and anthroquinone dyes;

[0020] - the radiosensitive molecule is chosen from: Leuco Crystal Violet (LCV), Leuco Malachite Green (LVM), or their derivatives;

[0021] - a distribution of the dose absorbed by said at least one film is determined according to at least minus two dimensions of the film;

[0022] - step a) consists of providing a stack of several radiosensitive films identical, each in the form of a solid polymer, namely a solid polymer doped with an activator and with a radiosensitive molecule also having radiofluorogenic properties, the stacking being carried out in a dimension perpendicular to the two main extension dimensions of a film, so that the implementation of said method results in obtaining a detection of the three-dimensional distribution of the radiation dose absorbed by said stack;

[0023] - the radiosensitive molecule also exhibits radiochromic properties. Brief description of the figures

[0024] Other characteristics and advantages of the invention will appear during the reading of the detailed description which follows for the understanding of which one will refer to the appended drawings and for which:

[0025] [Fig.l] is a flowchart of the steps of the method according to the invention;

[0026] [Fig.2] represents the chemical structure of triphenylmethanes;

[0027] [Fig.3] represents the chemical reaction transforming Leuco Malachite Green (LVM, uncolored) into malachite green (VM) in the presence of an activator and an energy source, namely ionizing radiation;

[0028] [Fig.4a] represents an absorbance spectrum of a solid polymer-based film (Sylgard 184®) before and after irradiation;

[0029] [Fig.4b] represents the absorption spectrum of the solid polymer-based film (Sylgard 184®) as a function of the dose, for each of the two peaks in Figure 4(a);

[0030] [Fig. 5] represents, for a given dose, the absorbance signal and the fluorescence signal obtained on a film based on a solid polymer with radiofluorogenic and radiochromic properties, as a function of the wavelength;

[0031] [Fig.6a] represents, for different doses, a measurement of absorbance of a film based on solid polymer, as a function of the wavelength;

[0032] [Fig.6b] represents, for different doses, a fluorescence measurement as a function of the wavelength and in accordance with the invention, with the film read in absorbance on [Fig.6a];

[0033] [Fig. 7] represents an absolute variation of a measurement signal representative of either a variation in absorbance or a variation in fluorescence of a solid polymer-based film read in accordance with the invention, as a function of the dose of ionizing radiation absorbed by the film; and

[0034] [Fig.8a] represents a two-dimensional measurement carried out on a radiochromic and radiofluorogenic film in the form of a solid polymer, with an absorbance response profile of an irradiated polysiloxane - LVM film;

[0035] [Fig.8b] represents a two-dimensional measurement carried out on the same film as that of [Fig.8a] radiochromic and radiofluorogenic in the form of solid polymer, with a fluorescence response profile. Detailed description of the invention

[0036] The invention relates to a method for determining a dose of ionizing radiation absorbed by a radiosensitive film in the form of a solid polymer.

[0037] A first step a) consists of providing a radiosensitive, and advantageously radiochromic, film in the form of a solid polymer, namely a solid polymer doped with an activator and with a radiosensitive molecule having, within the framework of the invention, radiofluorogenic properties.

[0038] In other words, the radiosensitive molecule exhibits fluorescence properties after irradiation.

[0039] The solid polymer may be selected from a set of polymeric materials generally known as optical plastics. This set of materials includes, but is not limited to, polysiloxanes, polyurethanes, poly(meth)acrylates (e.g., polymethyl methacrylate, PMMA), polystyrenes, cyclic olefin copolymers (COCs), polyolefins such as polymethylpentene, polycarbonates, epoxy resins, polyesters, and polysulfones. This set of materials also includes copolymers (e.g., poly(styrene-co-acrylonitrile)) and terpolymers (e.g., acrylonitrile butadiene styrene).

[0040] The activator's function is to provide the radical or ionic species necessary for activating the radiosensitive molecule. It is therefore just as necessary as the energy provided by the ionizing radiation. It may in particular be a halogenated compound.

[0041] The radiosensitive molecule is the molecule which undergoes a structural modification by the action of radical or ionic species resulting from the absorption of ionizing radiation by the activator and presents a change in its optical properties post-irradiation.

[0042] As already specified, in the context of the invention, the radiosensitive molecule has radiofluorogenic properties. For this purpose, it may in particular be chosen from at least one of the following families: diphenylmethanes and triphenylmethanes, fluoranes, diazonium salts, fulgides, fulgimides, diarylethenes, dithienylethenes, polydiacetylenes, oxazine leuco-dyes, spiropyrans, spirooxazines, chromenes and anthroquinone dyes.

[0043] Molecules of the triphenylmethane family are particularly well suited. This family of molecules is represented in [Fig.2].

[0044] And among the molecules of the triphenylmethane family, we can notably cite Leuco Crystal Violet (LCV) or Leuco Malachite Green (LVM), both of which are otherwise colorless before irradiation. In [Fig.2], we can also determine the chemical formulas of LCV and LVM from the general formula of the triphenylmethane family.

[0045] An example of a reaction transforming LVM (colorless radiosensitive molecule) into Malachite Green (VM, colored radio-induced molecule), in the presence of an activator, in this case halogenated, and an energy supply via ionizing radiation is shown in [Fig.3].

[0046] In Figure 4(a) the absorbance spectrum of a solid polymer film (Sylgard® 184, which is a polysiloxane) doped with LVM is shown. The VM typically has two absorbance bands (solid line), one at 427 nm and the other of significantly greater intensity at 627 nm. In this same Figure 4 (dotted line), it is verified that the LVM has almost zero absorbance over the entire range of the visible domain (400 to 800 nm), i.e. it is colorless. And in Figure 4(b), the absorbance of this same solid polymer film is shown as a function of the dose for each of the two absorbance bands in Figure 4(a).

[0047] And in [Fig.5], we can observe both the absorption and fluorescence behavior of this type of polysiloxane film doped with LVM. The results were obtained on a plate reader. This figure represents the absorbance and fluorescence spectra obtained, as a function of wavelength, on a SpectraMax iD3 microplate reader from Molecular Devices. The curves have been normalized relative to their maximum. It should be noted that the fluorescence spectra are obtained by exciting the material at 400 nm and 580 nm (absorption bands of the radiosensitive dye formed post-irradiation). We also note the presence of two peaks, one at 460 nm and the other at 660 nm. The first peak is attributed to a transition between an S2 state (excited state) to the ground state (S0). As for the second peak, it is attributed by the passage from the SI state (excited state of lower energy) to the ground state (S0).

[0048] A second step b) of the method according to the invention consists of measuring the fluorescence response of said film. Depending on the sensitive molecule used, this can most often be carried out in the near infrared, and / or the visible, and / or the ultraviolet.

[0049] A third step c) consists of irradiating said film. The irradiation is carried out with ionizing radiation which can be radiation of photons, protons and / or electrons.

[0050] A fourth step d) consists of measuring the fluorescence response of said film thus irradiated. The frequency range that can be used has been specified previously for step b).

[0051] Finally, a last step e) consists of determining a variation in fluorescence of said film between step d) and step b). It is this step which finally makes it possible to determine the dose of ionizing radiation absorbed by said film.

[0052] An advantage of the invention lies in the fact that the radiosensitive molecule retains, after irradiation, its fluorescence properties, as well as its radiochromic properties. It is therefore possible to perform a delayed reading in time of the fluorescence and absorbance properties of the irradiated material. This makes it possible to overcome a drawback that real-time reading by fluorescence can encounter: Cerenkov radiation, which generates a light signal that can be wrongly interpreted as the dose of ionizing radiation absorbed by the film. Furthermore, the fact that the radiosensitive molecule is in a solid polymer limits the post-irradiation diffusion phenomena of the radio-induced molecule. This contributes to the reliability and stability over time of the recorded fluorescence information.

[0053] Furthermore, within the framework of the invention, when the radiosensitive molecule is also radiochromic, it is also possible to implement the additional steps consisting of: B) measuring, between step a) and step c) the absorbance response of the film; D) measuring, after step c) the absorbance response of the film; and E) determining a variation in absorbance of the film between step D) and step B).

[0054] Steps B) and D) can advantageously be carried out in the visible and / or near ultraviolet range.

[0055] To evaluate the gain in sensitivity that can be provided by fluorescence reading, a dose study was carried out on the same formulation, comparing the responses obtained in absorbance and fluorescence on samples formed in spectrofluorimetric cuvettes. This is the subject of examples 1 and 2 presented below.

[0056] Example 1: One-dimensional (1D) measurements

[0057] A polysiloxane-based film (solid polymer) doped with 0.25% Leuco Malachite Green and 1% CHCl3 (activator) was prepared. For this purpose, the material was cast in a tank with dimensions lcm*lcm*4.5cm and crosslinked at room temperature, protected from light for two days. The radiosensitive molecule used here is therefore not only radiofluorogenic, but also radiochromic.

[0058] Irradiation conditions

[0059] For the conduct of the test, the following conditions were applied.

[0060] The ionizing radiation source used is a Versa HD accelerator from Elekta. The correspondence between the internal units controlling the accelerator and the dose in Gray is measured with a calibrated PTW30013 ionization chamber. The source was also set with an acceleration voltage of 6 MV and a dose rate of 5 Gy / min.

[0061] The film is placed at a distance of 100 cm from the source of ionizing radiation. The film is also in contact with a 2.5 cm thick polymethylmethacrylate (PMMA) plate, located between the film and the source of ionizing radiation. The source - skin distance is therefore 97.5 cm.

[0062] Tank reading conditions

[0063] The change in color of the radiosensitive molecule is monitored using a Cary 60 UV-Vis spectrophotometer from Agilent Technologies, before and after irradiation, which makes it possible to calculate the variation in the signal caused by the irradiation.

[0064] Fluorescence monitoring is carried out using a Horiba Jobin-Yvon Fluoromax 4P spectrofluorimeter (150W Xe lamp, simple monochromators).

[0065] The results are provided in Figures 6(a) and 6(b), respectively for the absorbance and fluorescence measurements.

[0066] In absorbance, we note the presence of two peaks, one at 425mm and the other at 627mm. This is entirely consistent with the known behavior of Malachite Green (see figures 4 and 5).

[0067] In fluorescence (ordered in arbitrary units), we also note the presence of two peaks, one at 460nm and the other at 660nm. The first peak is attributed to a transition between an S2 state (excited state) to the ground state (S0). As for the second peak, it is attributed by the passage from the SI state (excited state of lower energy) to the ground state (S0). This is consistent with what is presented in [Fig.5].

[0068] These different results make it possible to express the dose response of the film.

[0069] This is what is represented in [Fig.7] where we find, on the abscissa, the dose of ionizing radiation absorbed by the film and on the ordinate a parameter common to the two types of measurement carried out (fluorescence and absorbance).

[0070] This common parameter Aabsoiu is written:

[0071] A absolute Sample / Witness

[0072] With:

[0073] Sample = MAX(after irradiation) - MAX(before irradiation); and

[0074] Witness = MAX witness (after irradiation) - MAX witness (before irradiation)

[0075] The control is a non-irradiated control tank. This measurement allows, for the samples (film in its tank), a correction which would be linked to a possible evolution of the tank over a period of time elapsed between the irradiation and the reading of the microplate.

[0076] [Fig.7] is representative of the dose sensitivity of the film in question (slope).

[0077] Thus, for the absorbance, we have a slope of 1.778 Gy '.cm '. This slope is determined with the absorbance band at 627 nm which is the one of the two peaks which allows the greatest sensitivity to be achieved.

[0078] For fluorescence, it should be noted that the dose response is linear. Furthermore, a slope of the line at 6.299 Gy '.cm is noted. This slope is indeed that which is determined for the emission band at 660 nm from the results in Figure 6.

[0079] Thus, reading by fluorescence proves to be approximately 3.5 times more sensitive than reading by absorbance.

[0080] End of example 1.

[0081] Example 1 above focuses on providing one-dimensional (1D) data.

[0082] However, the method according to the invention may be used to determine a distribution of the dose absorbed by the film in at least two dimensions (2D).

[0083] Indeed, completely conclusive 2D tests have been able to be carried out. This is notably the subject of example 2 below.

[0084] Example 2: two-dimensional (2D) measurements

[0085] A preparation identical to that of the example of a radiofluorogenic and radiochromic (LVM) solid polymer (polysiloxane) film was made.

[0086] The device used is the same, with the exception of the accelerator (source of ionizing radiation), in this case a Cyberknife®, a source-skin distance of 75cm (which corresponds to an isocenter equivalent of 80cm for this accelerator). The dose rate is 1000 UM / min, i.e. 8.8 Gy here, and the acceleration voltage is 6MV.

[0087] Fluorescence and absorbance monitoring were performed using a SpectraMax iD3 microplate reader (Molecular Devices). Fluorescence intensities were measured at the emission maximum (660 nm) by exciting the microplate at 580 nm, with a spatial resolution of 1.8 mm. Absorbance intensity is read at 627 nm with a spatial resolution of 1.13 mm.

[0088] A comparison of the absorbance and fluorescence measurements is presented with Figures 8(a) and 8(b)

[0089] End of example 2.

[0090] Furthermore, according to a variant of the method according to the invention, step a) may consist of providing a stack of several identical radiosensitive films. Each radiosensitive film is then in the form of a solid polymer, namely a solid polymer doped with an activator and with a radiosensitive molecule also having radiofluorogenic properties, and advantageously also radiochromic properties. The stack is itself produced along a dimension perpendicular to the two main extension dimensions of a film, so that the implementation of said method results in obtaining detection of the three-dimensional (3D) distribution of the radiation dose absorbed by said stack.

[0091] The stacking can in particular be carried out according to what is described in document WO 2021 / 0023393. Other solutions could however be envisaged.

[0092] It should be noted that very recently, some authors have proposed dosimeters based on fluorescence measurement with the aim of characterizing the linearity of their dose response, their sensitivity limit and their sensitivity.

[0093] The proposed solutions are however based not on a solid polymer type film, but on a gel type polymer with a particular composition (surfactants, halogenated derivatives).

[0094] Thus, for example, Mochizuki et al., Sensitivity enhancement of DHR123 radio-fluorogenic nanoclay gel dosimeter by incorporating surfactants and halogenides, RSC Adv., 2020, 10, 28798-28806, propose a formulation (gel) based on DHR123 with a surfactant and a halogenated derivative judiciously chosen and proportioned for this purpose. They obtain a radiofluorogenic dosimeter with good linearity in the 0 to 4Gy range and a sensitivity limit (of the order of 0.01 Gy) comparable to that of a GAFchromic™ type radiochromic film, which operates with an absorbance measurement. However, no comparison is made on the sensitivity of the dosimeter thus obtained, compared to that of a GAFchromic™ type film. The sensitivity limit, similar in both cases, suggests comparable sensitivity. In addition, the authors mention a difficulty in using this type of dosimeter in two dimensions.This is possibly related to the use of a gel in which the dye tends to diffuse post-irradiation.

[0095] In the context of the invention, a completely different solution is finally reported, notably based on a solid polymer matrix, in which the sensitivity is clearly increased with a florescence reading compared to an absorbance reading. A 2D or even 3D reading is also reported to be entirely possible, while maintaining this improvement in sensitivity over time. Finally, a linearity zone between the dose and its response is reported to be more significant (the tests were carried out up to 12Gy).

Claims

Claims

1. Method for determining a dose of ionizing radiation absorbed by a radiosensitive film in the form of a solid polymer, characterized in that it comprises the following steps: a) providing at least one radiosensitive film in the form of a solid polymer, namely a solid polymer doped with an activator in the form of a halogenated compound and with a radiosensitive molecule also having radiofluorogenic properties; b) measuring the fluorescence response of said at least one film; c) irradiating said at least one film; d) measuring the fluorescence response of said at least one film thus irradiated; e) determining a variation in fluorescence of said at least one film between step d) and step b), this finally making it possible to determine the dose of ionizing radiation absorbed by said at least one film.

2. Method according to claim 1, the radiosensitive molecule of the film provided in step a) also having radiochromic properties, the method then comprises the additional steps of: B) measuring, between step a) and step c), the absorbance response of said at least one film; D) measuring, after step c), the absorbance response of said at least one film; and E) determining a variation in absorbance of said at least one film between step D) and step B).

3. Method according to the preceding claim, in which steps B) and D) are carried out at least in the visible range and / or in the near ultraviolet.

4. Method according to one of the preceding claims, in which steps b) and d) are carried out in the near infrared and / or the visible and / or the ultraviolet.

5. Method according to one of the preceding claims, in which the solid polymer is a polymer based on polysiloxanes, polyurethane, poly(meth)acrylates, for example polymethyl methacrylate (PMMA), polystyrenes, cyclic olefin copolymers (COC), polyolefins, polycarbonates, epoxy resins, polyesters, polysulfones, or copolymers such as styrene-acrylonitrile or terpolymers such as acrylonitrile butadiene styrene (ABS).

6. Method according to one of the preceding claims, in which the radiosensitive molecule is chosen from at least one of the following families: diphenylmethanes and triphenylmethanes, fluoranes, diazonium salts, fulgides, fulgimides, diarylethenes, dithienylethenes, polydiacetylenes, oxazine leuco-dyes, spiropyrans, spirooxazines, chromenes and anthroquinone dyes.

7. Method according to one of the preceding claims, in which the radiosensitive molecule is chosen from: Leuco Crystal Violet (LCV), Leuco Malachite Green (LVM), or their derivatives.

8. Method according to one of the preceding claims, in which a distribution of the dose absorbed by said at least one film is determined according to at least two dimensions of the film.

9. Method according to the preceding claim, in which step a) consists of providing a stack of several identical radiosensitive films, each in the form of a solid polymer, namely a solid polymer doped with an activator in the form of a halogenated compound and with a radiosensitive molecule also having radiofluorogenic properties, the stack being produced in a dimension perpendicular to the two main extension dimensions of a film, so that the implementation of said method results in obtaining detection of the three-dimensional distribution of the radiation dose absorbed by said stack.

10. Method according to the preceding claim, in which the radiosensitive molecule also has radiochromic properties.

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