Improving Brain Tumor Treatment through Nanotechnology and Proton Therapy Using Laser-driven Accelerators through GEANT4 Simulation

Introduction

Cancer beam therapy with charged particle beams, called particle therapy, is a new treatment method that has major advantages compared to conventional radiotherapy. Since ions have special ballistic properties and higher biological effectiveness, they are superior to X-rays. Numerous medical centers in the world use not only protons but also carbon ions as medical beams. Numerous researchers are trying to reduce the cost/benefit ratio and increase the treatment range. The main condition of particle therapy is to cause minimal damage to healthy tissues located at the entrance of the ion path before reaching the tumor. Therefore, a major challenge to improve tumor targeting is to focus the radiation on the malignant tumor. A new strategy is to add nanoparticles (NPs) to the tumor and then target it, which has been proposed for more than a decade to improve the performance of conventional photon therapy. Recently, many developments have been made in particle therapy and the amount of research is currently increasing and the promising results of this strategy are elucidating the underlying mechanisms.

The application of nanotechnology in radiotherapy also offers several interesting approaches to improve the therapeutic index. For instance, the loading of tumors with NPs containing high-Z isotopes can be used to enhance the effectiveness of irradiation with X-rays, exploiting the fact that the cross-section of the photoelectric effect scales as Z³. Another suggested mechanism promoting radiosensitization is the use of metal ions as a catalyst for reactive oxygen species which can increase the oxidative stress in cancer cells. Moreover, molecules such as liposomes, albumins, and graphene nanotubes could be used as carriers to deliver radio-sensitizing drugs or therapeutic radioisotopes to the tumor sites throughout the body, whereas other NPs like cerium oxide acting as free-radical scavengers could be used as radioprotectors in normal tissue.

Numerous experiments provide continuous evidence of a significant enhancement of the effects of ion irradiation in the presence of NPs. With the implementation of this strategy for cancer treatment, simulation studies have begun to rationalize and investigate the characteristics of this phenomenon. In addition, these studies help to introduce possible mechanisms and predict the effects of ion beams and the properties of NPs. Many questions that are still unresolved can be partially resolved by studying this effect, and even the findings of this type of study can be encouraging and open new challenges. NPs have been proposed as a more efficient measure to improve the concentration of active products in the tumor and thus improve tumor targeting through radiation effects. When targeting a tumor containing NPs by a proton beam, antibodies or peptides that constitute tumor cells are affected. Therefore, the combination of radiation therapy with nanomedicine opens up a new spectrum of treatments.

Hainfeld et al. were the first to show that a core of 1.9 nm gold NPs extended the lifespan of mice treated with 160 kV X-rays.[1] Polf et al. investigated the placement of 44 nm NPs in a tissue-equivalent phantom at a concentration of (“1”) ng/cell.[2] They found an increase in the efficacy of tumor cell killing by 15%–20% by proton irradiation with an energy of 160 MeV. Gold NPs are now well-known as a target material. Other advanced NPs made from other heavy elements such as hafnium[3] and gadolinium[4] are currently being brought to the clinic by Nanobiotix (Paris, France) and NH TherAguix (Villeurbanne, France).

Wälzlein et al. performed simulations to investigate the possible effect of proton dose enhancement with electron irradiation in the vicinity of high-Z NPs.[5] A number of biological studies support the apparent dose enhancement in the simulations. Kim et al. studied a mouse model using gold and iron NPs irradiated with protons at 45 MeV;[6] they found a 58%–100% survival rate with NPs compared to an 11%–13% survival rate with the beam. A number of studies have been conducted on the use of NPs in conjunction with proton beams, including some Monte Carlo simulations. Wälzlein et al. simulated a nanosphere of controlled materials surrounded by water with a proton dose increase of about 2 times for gold and platinum at 80 MeV.[5]

Another Monte Carlo study conducted by Gao and Zheng in 2014 on a gold NP in a simulated water phantom,[7] concluded that the production of secondary electrons increased with decreasing proton energy; whereas the average kinetic energy of secondary electrons generated by gold NPs increased with proton energy. Lin and colleagues in 2014 demonstrated a difference in the enhancement mechanism between photon-NP interactions and proton-NP interactions using Monte Carlo simulations,[8] where they found that proton-NP interactions had the highest enhancement. Lin and colleagues in 2015 proposed a biological model,[9] which requires higher NP concentrations for protons to achieve the same effect compared to photons for the additional cores of gold NPs enriched in cells.

Kwon et al. also simulated a gold NP in water in 2015.[10] However, they considered the radial dose distribution with respect to secondary electrons and found that the effect of gold NPs extended beyond a few micrometers in the longitudinal direction and a few nanometers in the radial direction. Since X-ray irradiation damages healthy and adjacent tumor tissues, treatment with high-energy ions such as protons (proton therapy) has been proposed as an alternative.[11121314151617]

The main advantage of ion beams comes from their ability to penetrate tissues for several centimeters and to deposit maximum energy at the end of their path, where the ionization cross-section of the medium is very large and a Bragg peak[12181920212223242526] is formed at a depth that depends on their initial energy. Therefore, proton beams can be tuned to target the tumor without damaging deeper tissues [Figure 1].

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Figure 1 Illustration of (a) highly penetrating X-ray beam propagation causing damage to healthy tissues, (b) ballistic effects of protons with negligible radiation effects after the tumor, but significant effects at the entrance to the path, and (c) enhanced effects of proton radiation on the tumor in the presence of nanoparticles, which opens the possibility of reducing the dose to the patient and placing the dose in tissues that are located before reaching the tumor

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Particle therapy in particular can be up to four times more effective than X-rays in some cases.[13272829303132] As a result, particle therapy is superior to conventional radiotherapy for at least some indications,[143233343536] and despite the high costs, new proton therapy centers are being developed around the world. Particle therapy is performed in two different ways. One method is the passively modulated broad beam modality, which involves a shaped beam at the target with a spread out of Bragg peak (SOBP).

The second method is the pencil beam active scanning mode, in which a multimillimeter beamlet is scanned point by point over the tumor and modulates the energy for each depth slice.[373839] According to studies, the presence of NPs in the studied environment improves the dose. As a result, activating a real tumor by NPs to improve the dose and, naturally, improve the treatment is very promising. Therefore, calculations of dose improvement in a tumor activated by gold or even silver and platinum NPs (PtNPs) are necessary for a more accurate evaluation of this treatment method. Therefore, in this work, we decided to provide a more complete and realistic study of brain tumor treatment by proton pencil beam with and without injection of gold, silver, and PtNPs, which has not been done so far, and to select the optimal conditions.

Laser-driven Proton Acceleration as a Novel Concept for Acceleration of Clinical Particle Beams

Laser-driven acceleration seeks to increase acceleration efficiency through the use of very high field gradients which in this case can theoretically exceed 1 GV/m. For the approach of target normal sheet acceleration, the backside of a thin target foil is illuminated with short pulses of a powerful laser which creates a plasma field and causes the electrons to emerge from the front surface of the foil. This creates an intense electrostatic field which pulls out and accelerates the actual beam particles (typically protons). Another approach, called radiation pressure acceleration, uses larger laser fields to turn the entire foil into a plasma. A crucial advantage of laser-driven systems is that conventional particle beam transport lines involving heavy electromagnets could be replaced by much lighter laser-guiding solutions. Such optical systems are easier to align, require less radiation shielding and could open up the possibility for lighter and smaller gantry designs. On the other hand, there are still many technical problems to overcome, in particular regarding the large energy spectrum of the emerging particles as well as the generation of clinically relevant beam energies and intensities. A promising project in this context is the Laser-hybrid Accelerator for Radiobiological Applications (LhARA) which is currently being developed at Imperial College London, UK. This machine is designed to accelerate protons as well as heavier ions in two stages delivering maximum proton beam energies of 15 and 150 MeV, respectively. First simulations have shown that LhARA could provide beams with exceptionally small emittances which makes this accelerator concept particularly attractive for the generation of clinical proton minibooms.

Combination of Nanoparticles with a Proton Beam

The effectiveness of high-Z NPs to enhance the performance of proton irradiation was first demonstrated by Reaz et al.,[15] who injected small NPs (1.9–14 nm in diameter) composed of gold or iron into tumors of mice that were simultaneously being treated with fast protons at 45 MeV and observed that the absorbed dose to the tumor and the resulting killing of cancer cells increased. The efficacy of gold in enhancing the effects of proton irradiation was confirmed in vitro by Polf et al.,[2] who observed a significant increase in the mortality of prostate tumor cells with 160 MeV protons when loaded with gold-containing nanosackfold phage (44 nm in diameter, 1 ng gold per cell).

Recent molecular scale experiments with platinum and gadolinium NPs activated by 150 MeV protons have shown enhanced nanobioenhancement.[16] Here, the role of hydroxyl radicals was demonstrated. Most importantly, the radioenhancement effects were greater at the end of the ion path. Tran and colleagues simulated a 50 nm diameter gold spherical particle in a water medium and subjected it to proton irradiation with energies between 2 and 170 MeV.[17] According to their results, the presence of NPs increased the absorbed dose in that region. Martinez-Rovira and Pezado also simulated larger phantoms.[18] They concluded that the dose enhancement decreases as the size of the studied environment increases, and therefore, the radiation activation results obtained in biological studies cannot be due to physical factors alone, but other factors, such as chemical and biological processes, may play a major role in increasing the damage to activated cells. Their study suggests more accurate calculations based on more realistic conditions.

It should be noted that in the simulations that have been performed so far, the energy has been adjusted in such a way that the proton particles pass through the area containing the NPs to study the effect of the interaction between the two on the dose improvement. Since these simulations do not consider the actual shape of a tumor, the composition and sequence of the head tissues, and the actual conditions of proton therapy, the absorbed dose improvement is not predicted, and these results are the achievement of the research presented in this article. Considering that conducting experiments in a real tumor has its own problems and is expensive, evaluating this treatment method using experimental experiments is not cost-effective. On the other hand, the Monte Carlo simulation method under GEANT4 is a conventional method for simulating particle transport. Therefore, in the next section, we will briefly introduce the GEANT4 simulator software.

The Proposed Phantom of Water and Head

We consider a cubic water phantom with dimensions of 30 cm × 30 cm × 30 cm, which is placed in a cube of air with dimensions of 200 cm × 200 cm × 200 cm. The overall geometry of the head phantom used in this study is a cube with a skin layer of 2 mm thickness, the soft tissue of 3 mm thickness, the skull of 10 mm thickness, the brain of 100 mm thickness, and finally soft tissue of 5 mm thickness. The distance between the source plate and the head phantom is kept constant at 15 cm. In this study, a 2 cm tumor is placed at a depth of 5 cm from the head phantom. Here, we used ideal assumptions for the selection of this phantom and used a similar phantom as given in Ref.[19] For a better understanding of the selected phantom and the tumor, see Figure 2 was added to Section 3 of the article. The type and composition of the tissues forming the brain and tumor in terms of mass percent of the elements used in the head phantom are given in Table 1.[20] The brain tumor is activated by a homogeneous distribution of gold NPs with concentrations of 10, 25, 50, and 75 mg/ml.[202122] Here, the lateral dimensions of the head phantom are considered to be 17.2 cm and 13.2 cm.[23] In this work, a pencil beam with a point scanning feature is used. Moreover, to simulate the proton beam, a circular source with a radius of 0.01 cm is placed at a distance of 15 cm from the head phantom. The irradiated proton beam contains 10⁵ protons.

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Figure 2 Schematic view of the head phantom used for proton therapy simulations

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Findings and Results

High-Z nanomaterials have previously been shown to increase the dose delivered to the tumor due to the increase in secondary electrons. This paper investigates the effects of high-Z nanomaterials in combination with protons and the influence of proton energy, material, and NP concentration. In this work, NPs are introduced with strong potential for dose enhancement in proton therapy, but the changes in Bragg peak distribution that occur at high concentrations need to be taken into account to ensure tumor coverage. Note that most simulations conducted so far have been to investigate the effect of simultaneously adding NPs to the proton beam. Hence, they have considered particles such as gold, silver, and platinum in nanoscale sizes and often in an aqueous environment. For this purpose, we aim to confirm the accuracy of dose enhancement with simultaneous proton beam irradiation and NP injection.

Our calculation results using the GEANT4 code simulation show that by changing the energy of the proton beam from 15 to 250 MeV, only protons with an energy of 150 MeV create the Bragg peak in the phantom. Therefore, in the figure, we have compared and presented the results obtained regarding the absorbed dose with a proton beam irradiation of 10⁵ particles without injecting NPs into the water and with injecting gold, silver, and PtNPs with densities of 10, 25, 50, and 75 mg/ml into the water at a proton energy of 150 MeV. As can be seen, the use of NPs simultaneously with the proton beam improves the dose and increases the absorbed dose rate for increasing the concentration of the NPs. This is due to the fact that NPs with high Z, such as gold NPs, increase the dose deposited inside the tumor or material due to the increase in secondary electrons.

The increase in absorbed dose is also due to the density effect, which means that the distance collisions that occur between charged particles and atomic electrons are affected by the interference of their atoms. These atoms are polarized in the electric field of the charged particles and reduce the electric field of the electron at the distance of the collision, and as a result, they cause a decrease in the stopping power. Since relativistic effects increase the importance of distance collisions, the importance of this effect increases at high energies. This effect depends on the number of polarized atoms per unit volume and, consequently, on the density of the materials, and is therefore called the density effect. Usually, the ratio of the mass stopping power in two materials changes slowly with the particle energy, but if one of the materials in question is a solid and the other is a liquid or gas, this ratio will change due to the decrease in the mass stopping power of the solid when the energy of the particles approaches the relativistic limits.

It is shown in Figure 3 that in Figures 3a-c, water alone without the injection of NPs has the lowest absorption dose, but gradually with the increase in the concentration of NPs from 10 to 75 mg/ml in water, the absorption dose changes and the location of the Bragg peaks moves toward a lower penetration depth with the increase in the concentration of injected NPs. Furthermore, PtNPs injected into water at an energy of 150 MeV proton have the highest absorption dose, followed by gold NPs injected into water, followed by gold NPs (AuNps) injected into water, followed by silver NPs (AgNPs) injected into water, and water alone without the injection of NPs has the lowest amount. This is because the highest secondary electron production occurs first for the injection of PtNPs into water, then for the injection of gold NPs into water, followed by the injection of AgNPs into water, and the lowest secondary electron production occurs in water only without the injection of NPs. Figure 4 shows the variations of absorbed dose in terms of penetration depth and proton beam energy in the proposed brain phantom without NP injection. From this figure, we see that by increasing the proton beam energy and penetration depth, the absorbed dose is decreased.

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Figure 3 Changes in absorbed dose resulting from simultaneous injection of a proton beam into water (w) and by injecting nanoparticles of (a) platinum, (b) gold, and (c) silver into the proposed water phantom for concentrations of 10, 25, 50, and 75 mg/ml depending on the penetration depth at a proton energy of 150 MeV. (a) Pt and Water, (b) Au and Water, (c) Ag and Water

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Figure 4 Variations of absorbed dose in terms of penetration depth and proton beam energy in the proposed brain phantom without nanoparticle injection. NPs: Nanoparticles

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Furthermore, in Table 2, for a better review of the results, the location of the Bragg peak and the numerical values of the absorbed dose in the water environment with the proton beam without the injection of NPs and with the injection of platinum, gold, and AgNPs are compared and given.

Furthermore, from observing Figures 5–8, it is found that in the range of injecting NPs with a concentration of 10–75 mg/ml into the brain tumor in the proton energy range of 50–140 MeV, the highest absorbed dose is obtained by injecting PtNPs into the brain tumor, followed by injecting gold NPs into the brain tumor, and the lowest is obtained by injecting AgNPs into the brain tumor. As mentioned, this is due to the production of secondary electrons. By injecting PtNPs into the tumor, the most secondary electrons are produced, and then by injecting gold NPs into the tumor, a smaller amount of secondary electrons are produced, and the lowest amount of secondary electrons are produced by injecting AgNPs into the brain tumor. It is also seen that with increasing the concentration of NPs into the brain tumor, the absorbed dose in the tumor increases. And considering that the tumor is 2 cm thick and is located 5 cm deep from the head phantom, the optimal energy that is deposit at the end of the tumor Bragg curve is the 110 MeV proton energy.

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Figure 5 Comparison of absorbed dose variations versus penetration depth and proton beam energy in the proposed brain phantom with an injection of (a) platinum, (b) gold, and (c) silver nanoparticles at a concentration of 10 mg/ml with a diameter of 50 nm. PtNPs: Platinum nanoparticles, AuNPs: Gold nanoparticles, AgNPs: Silver nanoparticles

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Figure 6 Comparison of absorbed dose variations in terms of penetration depth and proton beam energy in the proposed brain phantom with an injection of (a)platinum, (b)gold, and (c)silver nanoparticles at a concentration of 25 mg/ml with a diameter of 50 nm. PtNPs: Platinum nanoparticles, AuNPs: Gold nanoparticles, AgNPs: Silver nanoparticles

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Figure 7 Comparison of absorbed dose variations in terms of penetration depth and proton beam energy in the proposed brain phantom with an injection of (a)platinum, (b)gold, and (c)silver nanoparticles at a concentration of 50 mg/ml with a diameter of 50 nm. PtNPs: Platinum nanoparticles, AuNPs: Gold nanoparticles, AgNPs: Silver nanoparticles

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Figure 8 Comparison of absorbed dose variations in terms of penetration depth and proton beam energy in the proposed brain phantom with an injection of (a)platinum, (b)gold, and (c)silver nanoparticles at a concentration of 75 mg/ml with a diameter of 50 nm. PtNPs: Platinum nanoparticles, AuNPs: Gold nanoparticles, AgNPs: Silver nanoparticles

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In summary, we initially selected the proton beam energy in the interval 10–250MeV and performed our simulations but the obtained results from this study show that for proton beam energy interval 50–140 MeV we have the proper situation for treatment of this tumor. Furthermore, the results of our simulations showed that if a proton beam with an energy of 110 MeV is irradiated to tumor in a selected phantom, its Bragg peak will form completely in the tumor and deposit its energy at the end of the tumor, which is known as the optimum energy.

Simulated longitudinal shift and Bragg peak width narrowing: High concentrations resulted in significant changes to the shape of the Bragg peak [Figures 5-8]. The longitudinal shift for both energies is presented in Table 3. The highest shift was found to be for Pt at 110MeV with a concentration of 75 mg ml⁻¹.

Some recent studies tried to explore the potential application of metallic NPs in various therapeutic and diagnostic physics.[202122232425] Due to their high atomic number (Z), thus, high photoelectric coefficient, the metallic NPs such as gold, platinum, and silver have been investigated as dose enhancement agents in radiotherapy.[202122] Because of their high photon stability and high quantum yield, they have been examined for the use as contrast agents in medical imaging.[232425] Furthermore, it has been shown that a metallic foil (e.g., Au) surface enhances relative biological effectiveness because of metal’s high secondary electron production efficiency,[26] so it can be expected that the surface of a metallic NPs will cause a similar enhancement The essential of such metallic NP studies in radiological physics are related to its specific characteristic of secondary electrons produced by irradiation. In photon therapy and diagnostic imaging, photoelectric and Compton scattering effects are dominant in the secondary electron production. In proton therapy, proton-induced ionization plays the dominant role in secondary electron production. The mechanism of proton-induced ionization has been depicted in early pioneer literature.[2728] Here we just brief the picture of this interaction. When a proton approaches an atom, due to the opposite charge of the proton and orbital electron, the orbital electron will be pulled out from the atom. After a proton passes through the electron cloud, some orbital electrons still keep following the proton and leave the atom. Only when the proton energy is low enough and its speed is close to the speed of orbital electron, orbital electron can be captured by the passing protons (different from the nuclear electron capture). This electron capture is only dominant at low energy (<100 keV). As a proton passes through a metallic NP, secondary electrons are produced both inside and outside the NP. Because of the high electron volume density (numbers/volume) inside of the metallic NP, more secondary electrons are generated inside the metallic NP than outside. However, some of the internal electrons will fly outside the NP if their energies are high enough to overcome the surface work function. Detailed information about the secondary electron production distribution is thus crucial in microdosimetry. The atomic numbers of Gold, platinum, and silver are 79, 78, and 47, respectively. It should be noticed that based on the irradiation energy, various materials will produce different secondary electrons. It is as a result of different absorption cross-sections.[11] It is commonly understood that the main factor causing NP-induced dose enhancement is the resulting increase in the number of secondary electrons. Our model corroborates with this as shown in Figure 9, where an increase in the number of secondary electrons could be observed with an increase in NP concentration for both energies.

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Figure 9 Number of generated secondary electrons with increasing concentration for all materials with (a) 70 MeV beam and (b) 110 MeV

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Therefore, the findings presented have the potential to be observed clinically. As such if NPs are used clinically and this localization is achieved, treatment plans would then need to take these changes into account to ensure an accurate plan. Shifts in the Bragg peak have potential to under-dose or miss irradiation of the tumor target. With the introduction of NPs, the cumulative effect on the uncertainties has not been previously evaluated.

Among the various metallic NPs explored, those containing elements such as gold and silver are highly studied due to their unique physical properties, biocompatibility, and stability under physiological conditions.[22] However, NPs such as PtNPs, and AgNPs, have also demonstrated radio sensitization capabilities, although with distinct advantages and limitations [Table 4].

Conclusion

As is clear from this study, there is a potential for increasing the proton dose from injecting NPs into water or brain tumors; however, the most important optimal parameters in this type of treatment are related to the choice of the type of NPs, the concentration of their injection into the water and the selected brain tumor, the size of the NPs, and the optimal determination of the proton beam energy. In summary, the above studies showed that the level of absorbed dose increase is affected by the size, concentration, type of NPs, and beam energy. Scientists showed[24] that the cellular tissue uptake of NPs through interpolation of the size of the NPs is dependent on the optimal size of 50 nm, which of course our calculations also give the best-absorbed dose in water and brain tumors for spherical NPs with a diameter of 50 nm[2526] and since Wälzlein et al.[5] in 2014, Gao et al.[7] in 2014 and Peukert et al. in 2020,[27] studied the simulation of three suitable materials for treatment gold (Au), silver (Ag), and platinum (Pt), all of which are compatible with each other and can be used for treatment, we also used three types of platinum, gold and AgNPs to treat brain tumors. As can be seen, the absorbed dose with the injection of NPs at an energy of 150 MeV is, in order, from highest to lowest, related to platinum, gold, silver, and finally water without the injection of NPs, and this is due to the fact that the number of secondary electrons produced by platinum is more than gold, gold is more than silver and silver is more than water (Pt>Au>Ag>W). Moreover, the optimum energy left in the Bragg curve at the end of the brain tumor is 110 MeV. The results of this study prove that the concentration of NPs is directly proportional to the number of secondary electrons emitted, and the production of additional electrons at short distances increases the absorbed dose. However, more evidence needs to be provided on the effect of NP concentration on biological tissues, so that the impact of secondary electrons can be evaluated in terms of the identified effective dose, which will be an important topic for future research. In conclusion, the incorporation of Au, Ag, and Pt NPs into proton therapy represents a significant evolution in radiotherapy, promising to enhance therapeutic outcomes through improved targeting, precision, and integration with complementary treatments. Continued research and clinical validation will be essential to translate these advancements into routine clinical practice, paving the way for innovative and personalized cancer therapies.