Gold Nanoparticles Enhancing Protontherapy Efficiency

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Gold Nanoparticles Enhancing Protontherapy Efficiency Lorenzo Torrisi* Dipartimento di Fisica & SdT, V.le F.S. D’Alcontres 31, 98166 S. Agata, Messina, Italy Received: April 08, 2014

Revised: December 18, 2014

Accepted: December 20, 2014

Abstract: The insertion of gold nanoparticles in biological liquids, tissues and organs permits to increase the equivalent atomic number of the medium that, if used as target to be irradiated by ionizing radiation, permits an increment of the absorbed dose. No toxic nanoparticles, such as the Au, can be injected in the cancer tissues at different concentrations before using a localized treatment that uses energetic proton beams for radiotherapy. Due to the high density and atomic number of the used gold nanoparticles, the absorbed radiation dose can be increased to about a factor six per cent using relatively low concentration of nanoparticles injectable as solution in the tumor tissue. This means to reduce the exposition to ionizing radiation or to increase the dose to the tumor site. Simulation programs of proton energy loss in tissues, using SRIM Code, are employed to evaluate the Bragg peak enhancing in presence of Au nanoparticles, so it will be presented and discussed. Some research findings and patents in the gold nanoparticle preparation and application to Medicine are reviewed in the present paper.

Keywords: Bragg peak, gold nanoparticles, ionizing radiation, protontherapy, radiotherapy, SRIM code.. 1. INTRODUCTION Generally nanoparticles are represented by microscopic particles between 1 and 100 nm, also if some definitions include particles of up to 1 µm size. Gold nanoparticles (GNP) can be employed for different reasons concerning the cancer therapy. One of this consists in their biocompatibility and in their use as drug carriers: GNP can be chemically bonded to complex molecules to be transported "in vivo" in some tissues and organs to induce high tumor growth inhibition [1]. The number of Patents in the field of GNP production and use in Medicine is in continuum growth, reporting application to GNP synthesis [2, 3], therapy [4, 5] and imaging [6, 7]. GNP can be employed for thermal therapy, such as hyperthermia. This represents a cancer treatment in which the diseased tissues are submitted to high temperatures, up to about 45 °C. The thermal treatment can damage proteins, induce shrink tumors and kill cancer cells, usually with minimal injury to normal tissues [8]. The GNPs properties, including high atomic and electronic density, high biocompatibility, sub-micrometric size, and ability to be chemically bonding to peculiar molecules, indicate high potentiality to be employed also as contrast agents. Often iodine is employed as contrast medium; it improves the volume definition of vascularized tumors. Using photons for radiotherapy, at energies above 100 keV, the mass attenuation coefficient, µ/ρ, of gold is higher with respect to the iodine, indicating that a higher contrast image *Address correspondence to this author at the Dipartimento di Fisica & SdT, V.le F.S. D’Alcontres 31, 98166 S. Agata, Messina, Italy; Tel: +390906265052; Fax: +39090395004; E-mail: [email protected] 1872-2105/15 $100.00+.00

can be obtained. At this photon energy the mass absorption coefficient for gold is 5.2 cm2 /g, while for the iodine is 1.9 cm2 /g, and for a soft tissue is 0.17 cm2 /g, so gold enhances significantly the contrast action with respect to other biocompatible media [9]. In vitro study using CT (Computer Tomography) and MRI (Magnetic Resonance Imaging) imaging using Gd and Au shows high absorption with respect to I, demonstrating that lower dose can be given to obtain high resolution images [10]. The choice to use Au, instead that Gd or I, is justified by the higher Z and density of the NP which induce high energy deposition of the ionizing radiation. GNP can be employed also as radiosensitizer because it increases the photoelectric absorption and Compton scattering by high-Z materials interactions. Particularly, Fig. (1) shows the differences between the mass coefficient absorption for soft tissues and gold with increasing the photon energy (a), the total stopping power of electrons (b) and of protons (c) for water equivalent tissues and gold targets increasing the particle energy, so as obtainable from the National Institute of Standards and Technology (NIST) database [11]. For photons high differences in the energy deposition are limited only to energies between some keV up to about 500 keV, while for electrons and ions remain high also at high kinetic energy. The maximum energy deposition differences are found for low energy protons in the nuclear energy loss regime, i.e. at the Bragg peak position. In radiotherapy if a high-Z material as GNP is injected at high concentration in the tumor, an improvement in the therapeutic index could be obtained. Literature shows that increasing the localized dose in the tumor, the radiosensitivity of the neovascular endothelial cells could be enhanced significantly [12]. © 2015 Bentham Science Publishers

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mors. Thus, healthy tissue damage is still the dose limiting factor that diminishes tumor cells eradication in radiation therapy. The beam energy release in healthy tissues is one of the major factors influencing the radiation therapy effectiveness. The interaction of ionizing radiation with GNPs generates ion and electron scattering, secondary electron emission and production of X-rays and Auger electrons with great energy deposition in the vicinity of nanoparticles. For photon treatments the cross section of interaction depends strongly on Z, when the photoelectric, Compton scattering and pair production occur, the cross-sections are proportional to Z4, Z and Z2 of atoms, respectively [14]. Consequently, it is expected that the interaction of X and γ rays with gold atoms deliver high energy to GNPs which is transformed to electrons emission and thermal energy. Electrons are stopped proportionally to the square of the atomic number of the target and to the target density, according to the Bethe formulation. Moreover, their stopping power is inversely proportional to the ionization potentials of the target atoms, according to the Bloch formulation. Thus electrons are stopped and scattered more in tissues containing GNP with respect to normal ones, and, according to literature, this effect increases with the GNP size, concentration and electron energy [15]. For ions the energy loss is also proportional to the square of the ion atomic number and of the target atoms, to the target density and inversely proportional to the ionization potentials of the target atoms. Ion beams produce high ionizations along their tracks and generate delta rays which cause multiple ionization of Au.

Fig. (1). Comparison of massive energy absorption coefficients vs. photon energy for gold and soft tissue (a), comparison of electron stopping power vs. electron energy for water and gold (b) and comparison of proton stopping power vs. proton energy for water and gold (c).

Moreover, a significant reduction in tumor volume compared to a control group can be obtained injecting metallic nanostructures in tumors and using traditional innovative radiotherapy (X-rays, electrons and ions) [13]. GNPs have high K-edge of gold which can lead to the emission of low-energy Auger electrons and photoelectrons upon irradiation with photons below 200 keV, to high Bremsstrahlung and stopping powers for therapeutic electrons and to high stopping powers and Bragg peaks for therapeutic ion beams. Radiation therapy, using X-rays, gamma rays, electron beams and high energy ions, is employed extensively for treatment of almost all types of tu-

The application of radiotherapy is associated with the problem of high skin and superficial dose and rapid drop off of absorbed dose with depth. Although photons and electrons can be good candidates for radiation beams therapy using GNP, some limitations occur because they produce high absorbed doses not only in the cancer tissues but also in the surface healthy tissue. A secure advantage can be obtained with hadrontherapy, which releases high dose mainly at the controllable Bragg peak position. For protons the Bragg peak is well localized for Au target with respect to water, depending on the initial proton beam energy, and the released dose significantly increased in depth with respect to the value released in surface, as it will be presented and discussed. 2. MATERIALS AND METHODS A Nd:YAg laser operating at 3 ns pulse duration, 1064 nm wavelength, 200 mJ pulse energy, 0.6 mm2 laser spot, 1010 W/cm2 intensity, operating in single pulse or at 10 Hz repetition rate was employed to prepare the Au nanospheres at the Physics Department of Messina University. Pure targets of Au were used as thin targets, 0.5 mm thickness and 5 mm x 5 mm flat surface, to be ablated in water or in liquid solution by the laser pulses. The preparation of NP was obtained by irradiating thin sheet of metal placed in water or in a liquid solution containing polyvinylpyrrolidone (PVP) and isopropanol as colloidal stabilizers. Laser beam has a diameter of 10 mm and travel horizontally in air; it hits a glass prism producing a beam deflection at 90° in vertical direction and, after a focalizing lens, reaches a beaker filled with 15 ml of liquid in the bottom of which it is well fixed the Au

Gold Nanoparticles Enhancing Protontherapy Efficiency

Recent Patents on Nanotechnology, 2015, Vol. 9, No. 1

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target. The typical experimental set up is reported in Fig. (2a) while Fig. (2b) shows a photo of the experimental apparatus. The mass of the ablated metal transformed in NP dispersed in liquid was measured as weight difference of the sheet before and after the laser irradiation. This last was obtained irradiating for 10 minutes at 10 Hz the metal sheet placed in the liquid i.e. using 6000 laser shots. Generally the GNP solution has a concentration of 10-100 mg of Au NP/15 ml water. The GNP solution, just after the preparation, was submitted to optical characterization in the UV, Visible and IR wavelength region 250-1000 nm. To this an Hg-Ar lamp was employed as light source with characteristic peaks and an optical spectrometer (Horiba Jobin Yvon) for measurements of light absorption through the solution. The optical absorption spectra allow measuring the excitation and the extinguishment wavelengths of light irradiating SPs (surface plasmons). Fig. (3a) shows the optical absorption spectrum of GNPs in water as obtained from optical spectroscopy at the Physics Department of Messina University. The absorption properties of medium containing GNP is dependent on the particle dimensions, distribution dimension, surrounding media and velocity of coalescence, as reported in literature [16]. Experimental spectra are in agreement with literature data, indicating that the mean GNP size should be around 20 nm, as reported in Fig. (3b) [17]. However TEM investigations indicate a mean dimension of about 40 nm, as reported in Fig. (9c). Probably this difference is due to a size distribution centered around 30 nm of the GNP with a fluctuation of the order of ± 20 nm, as obtainable from the comparison between Fig. (3a) and (3b). SEM and TEM microscopy have demonstrated that some GNP aggregates are also present in the solution and that their size may reach even 1 micron. In order to put in evidence the physical role of the GNP in water and in biological tissues and whether it is potentially useful for a more efficacious protontherapy, simulation programs using SRIM code of Ziegler were employed to calculate the proton energy loss vs. the target depth [18]. To convert the dose in water, D w, in a dose in solution containing GNP, DGNP, (or in a given tissue containing GNP) it is required to correct solely for the difference in stopping power, using the Bragg Gray cavity theory [19]:

Fig. (2). Scheme (a) and photo (b) of the experimental set-up used to

produce GNP.

Water Case

3. RESULTS

Using 100 MeV protons to irradiate water, the ion trajectories, the ion range and the ionization processes vs. depth can be plotted by SRIM code. Fig. (4a) shows a typical example of trajectories simulation using 2000 protons incident in H2O. The proton range is well localized to 76.1 mm depth and the straggling is 1.18 mm, as reported in the plot of Fig. (4b). The ionization curve, reported in Fig. (4c), shows that the proton energy loss is lower at the surface, where it assumes a value of about 0.8 MeV/mm and increases reaching a maximum at the Bragg peak, where it assumes a value of about 4.83 MeV/mm. Thus, the simulation shows that the proton energy loss ratio, R, between the Bragg peak value, (dE/dx)B, and the surface value, (dE/dx)S, is of about 6.04.

The usefulness of GNP in protontherapy will be demonstrated by Monte Carlo SRIM simulations that will be discussed in detail. Instead that in terms of deposited dose, in Gray unit, we will discuss in terms of energy loss of the energetic projectile, given in MeV cm2/g or MeV/mm. Using eq. (1) it will be possible to calculate the relative absorbed doses in different tissues.

Using a water solution at high GNP density, so as prepared in our laboratory, with a concentration of 100 mg Au NP in 1 cm3 H2O, i.e. using a concentration of 10% in Au weight corresponding to 0.3% in Au atoms, the solution shows a different behavior with respect to the proton energy loss in pure water. Fig. (4d) shows a typical example of trajectories simulation using 2000 protons incident in a first

dE (1 / ! )( )GNP dx = Dw " dE w (1 / ! )( ) w dx GNP

DGNP

Eq. (1)

where ρGNP and ρw represent the density of the solution or tissue containing the GNP and the water density, respectively, and the terms (dE/dx)GNP and (dE/dx)w represent the stopping power in the medium containing GNP and in the water, respectively.


Lorenzo Torrisi

MeV/mm and increases significantly at the Bragg peak, where it assumes a value of about 5.08 MeV/mm. Thus the simulation shows that the proton energy loss ratio, R, between the Bragg peak value, (dE/dx)B, and the surface value, (dE/dx)S, is of about 6.35, showing an increment of about 5.13% with respect to the pure water case. Adipose Tissue Case The case of soft tissue, water equivalent, such as the adipose tissue, with a stoichiometry according to the ICRP [20], having a density of 0.92 g/cm3 and a stoichiometry H12C64N1O23Na0.05Cl0.11, as given by the Ziegler SRIM Code [18], has been investigated. In this case Fig. (5a) shows a typical example of ion trajectories simulation using 2000 protons incident in the muscle. The proton range is well localized to 93.0 mm depth and the straggling is 1.15 mm, as reported in the plot of Fig. (5b). The ionization curve, shown in Fig. (5c), indicates that the proton energy loss is lower at the surface, where it assumes a value of about 0.7 MeV/mm and increases reaching a maximum at the Bragg peak, where it assumes a value of about 3.9 MeV/mm. Thus the simulation shows that the proton energy loss ratio, R, between the Bragg peak value, (dE/dx)B, and the surface value, (dE/dx)S, is about 5.57.

Fig. (3). Normalized absorption measurements vs. wavelength for GNP in water (10 mg/15 ml) (a), comparison with literature data (b) and TEM photo of GNP in PVP (c) depth, ion ranges and ionization.

layer thick 60 mm of pure water with a density of 1 g/cm3 and a subsequent layer (simulating an organ with GNP uptake) of 40 mm in thickness of H2O+GNP with 0.3% in Au atoms concentration, whose density is 1.1 g/cm3. The proton range is well localized to 75.5 mm depth and the straggling is 0.88 mm, as reported in the plot of Fig. (4e). Thus, the proton range practically is reduced to 0.079% with respect to water and the straggling is reduced to about 25%. The ionization curve, reported in Fig. (4f), shows that the proton energy loss at the surface remains to the value of about 0.8

Using a water solution at high GNP density, as prepared in our laboratory, with a concentration of 100 mg Au NP in 1 cm3 H2O, i.e. using a concentration of 10% in Au weight and of 0.3% in Au atoms, we assume that the solution can be injected, with a long syringe, in the soft adipose tissue that absorbs the solution recycling the water that now contains the GNP. The stoichiometry of the tissues remains the same but now the adipose tissue density of 0.92 g/cm3 can be increased to about 1.02 by the insertion of the 100 mg/cm3 of Au NP. In terms of concentration we have the Au at about 10 % in weight concentration. In terms of atomic concentration it means to have 3x1020 Au atoms per cm3 volume in which there are 4.73x1020 H12C64N1O23Na0.05Cl0.11 molecules, i.e. for each molecule we have 0.63 Au atoms, corresponding to an Au atomic concentration of 0.63%. With this assumption the SRIM simulation was obtained using 2000 protons incident in a first layer of pure adipose tissue, thick 70 mm with 0.92 g/cm3 density, and in a successive second layer, thick 30 mm with 1.02 g/cm3 density, in which the GNP were hypothetically injected. Fig. (5d) shows a typical example of ion trajectories simulation. The proton range is well localized to 91.8 mm depth and the straggling is 1.39 mm, as reported in the plot of Fig. (5e). Thus, the proton range decreases to about 1.3% while the straggling increases of about 20.87%. The ionization curve, reported in Fig. (5f), shows that the proton energy loss at the surface remains to the value of about 0.7 MeV/mm and increases significantly at the Bragg peak, where it assumes a value of about 4.15 MeV/mm. Thus the simulation shows that the proton energy loss ratio, R, between the Bragg peak value, (dE/dx)B, and the surface value, (dE/dx)S, is of about 5.93, showing an increment of about 6.5% with respect to the pure adipose tissue case. Spongiosa Bone Case Now consider the case of a hard tissue, such as the spongiosa bone irradiated with 100 MeV protons. This tissue



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Fig. (4). SRIM simulations for 100 MeV protons in water reporting the ion trajectories (a), the ion range (b) and the ionization processes vs. depth (c) and comparison with simulations relative to a target composed by 60 mm water and 40 mm GNP in water in terms of ion trajectories (d), range (e) and ionization processes vs. depth (f).

has a density of 1.18 g/cm3 and a stoichiometric composition Ca7H9C40N3O37P3S0.2Fe0.1, according to the Ziegler databook of SRIM [18]. Fig. (6a) shows a typical example of trajectories simulation using 2000 protons incident in spongiosa bone. The proton range is well localized to 75.9 mm depth and the straggling is 1.03 mm, as reported in the plot of Fig. (6b). The ionization curve, given in Fig. (6c), shows that the proton energy loss is lower at the surface, where it assumes a value of about 0.80 MeV/mm and increases reaching a maximum at the Bragg peak, where it assumes a value of about 4.86 MeV/mm. Thus the simulation shows that the proton energy loss ratio, R, between the Bragg peak value, (dE/dx)B, and the surface value, (dE/dx)S, is about 6.08. Using a water solution at high GNP density, as prepared in our laboratory, with a concentration of 100 mg Au NP in

1 cm3 H2O, i.e. using a concentration of 10% in Au weight and of 0.3% in Au atoms, we assume that the solution can be injected, with a long syringe, in the spongiosa bone that absorbs the solution due to its high porosity of recycling the water and absorbing the GNP. The stoichiometry of the tissues remains the same but now the spongiosa bone density of 1.18 g/cm3 is increased to about 1.28 g/cm3 by the injection of GNP. In terms of concentration we have the Au at about 10% in weight concentration. In terms of atomic concentration it means to have 3x1020 Au atoms per cm3 volume in which there are 4.69x1020 Ca7H9C40N3O37P3S0.2Fe0.1 molecules, i.e. for each molecule we have 0.63 Au atoms, corresponding to an Au atomic concentration of 0.63%. With this assumption the SRIM simulation was obtained using 2000 protons incident in a first layer of pure spongiosa bone thick


Lorenzo Torrisi

Fig. (5). SRIM simulations for 100 MeV protons in adipose tissue reporting the ion trajectories (a), the ion range (b) and the ionization processes vs. depth (c) and comparison with simulations relative to a target composed by 70 mm adipose tissue and 30 mm GNP in adipose tissue in terms of ion trajectories (d), range (e) and ionization processes vs. depth (f).

60 mm with 1.18 g/cm3 density and with a successive second layer thick 20 mm with 1.28 g/cm3 density in which the GNP were injected. Fig. (6d) shows a typical example of ion trajectories simulation. The proton range is well localized to 75.2 mm depth and the straggling is 0.83 mm, as reported in the plot of Fig. (6e). Thus the proton range decreases to about 0.9% while the straggling decreases to about 17%. The ionization curve, reported in Fig. (6f), shows that the proton energy loss at the surface remains to the value of about 0.80 MeV/mm and increases significantly at the Bragg peak, where it assumes a value of about 5.16 MeV/mm. Thus the simulation shows that the proton energy loss ratio, R, between the Bragg peak value, (dE/dx)B, and the surface value,

(dE/dx)S, is about 6.45, showing an increment of about 6.08% with respect to the pure skeletal cortical tissue case. We have not considered the high density bones, such as the cortical one because the nanoparticles are not practically injectable inside it and, at the use of high concentrations are not injectable in blood to be transported inside the bone. The proton energy loss ratio R is calculated as ratio between the energy loss value at the Bragg peak and at the surface. Of course R increases with the GNP concentration, until reaching the maximum value of 13.06 for an Au thin target, 0.5 mm in thickness, placed in water at 73 mm depth, corresponding to the Bragg peak position of 100 MeV incident protons.



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Fig. (6). SRIM simulations for 100 MeV protons in skeletal spongiosa bone tissue reporting the ion trajectories (a), the ion range (b) and the ionization processes vs. depth (c) and comparison with simulations relative to a target composed by 60 mm skeletal spongiosa bone tissue and 20 mm GNP in spongiosa tissue in terms of ion trajectories (d), range (e) and ionization processes vs. depth (f).

The proton energy loss ratio variation, ΔR (%) is measured as R variation using target without GNP and target containing GNP at the Bragg peak position. The proton energy loss ratio variation, ΔR (%), vs. proton energy, obtained from SRIM simulations, is reported in Fig. (7) for protons in water and for protons hitting water and GNP in water at the Bragg peak position. The figure indicates that the ΔR improvement can reach about 8% using 200 MeV protons with a Bragg peak localized at about 250 mm depth. This result, extended to the case of soft and hard biological tissues, indicates that it is plausible to reach increment of proton absorbed dose up to about 10%, due to the energy release in tissues containing

GNP at concentrations of the order of 100 mg/10 ml with respect to the normal tissue case. Of course, the ΔR (%) value depends on the GNP concentration and the use of other ions for hadrontherapy, such as carbon, due to their higher stopping powers in GNP which may further increases its value. The R values calculated by Monte Carlo SRIM simulation are affected by errors of the order of 1%. In real measurements such errors should increase of about one order of magnitude due to different causes such as the gradients in the medium density, the gradients in the GNP concentration in the target, the GNP size


distribution and the proton beam alignment and energy modulation with the tumor geometry.

Lorenzo Torrisi

to risk organs, a SRIM simulation can be lanced again using the real geometries and densities of the target, before the proton treatment, to use the optimal proton energy and to maintain the dose fluctuations lower possible also below the 10%. Thus, the efficacy of the proton therapy treatment will depend strongly on the spatial accuracy of the GNP injection in the tumor site and on the GNP absorption and diffusion in the target tissue. Fast liquid diffusion in the tissue may reduce the local GNP concentration and uniform metal distribution may alter the therapy efficiency in the tumor. In these cases the efficiency enhancement may be diluted and the risk to have an efficiency enhancement below 5% is high. It should be useful to increase the GNP concentration at higher values, if possible, assuming for example that the solution can be removed just after the radiotherapy process. The evaluated efficiency enhancement of the order of 5%-6% can be considered relevant for many clinical cases, as reported by literature [21].

Fig. (7). Proton energy loss ratio variation, ΔR (%), vs. proton energy. R is calculated as ratio between the energy loss value at the Bragg peak and at the target surface, while ΔR (%) is relative to the dose enhancement measured using targets without and with GNP at the Bragg peak position.

4. DISCUSSION AND CONCLUSIONS The reported simulation study indicates that injecting a solution containing high concentration GNP in the tumor tissue site, it is possible to increase significantly the released proton energy at the Bragg peak with a consequent ion dose increment ranging from about 5% (in liquids) to about 6.5% (in soft tissues). The given percentage of dose efficiency enhancement is well repeatable by using the Monte Carlo simulation SRIM code, as demonstrated by repetitive simulations performed by changing the number of protons in the range 103÷105. In this sense the variations are only of the order of 1%. However, higher fluctuations can be due to the medium density change with respect to the expected value and to the change of the solution concentration containing the GNP injected in the target tumor. The tissue density in fact may have local gradients due to physiology or to the pathological disease and the presence of interfaces may produce change in the uniform distribution of the nanoparticles in the target, as a consequence of the different diffusion coefficient in different media. Generally,interfaces increase the local GNP concentration with risk that higher doses can be released to their site. These effects may produce little shift of the Bragg peak position and of the surface-target dose ratio. Generally, if preventive analyses, such as that based on X-ray absorption, are employed before the ion treatment, the expected fluctuations on the released dose can be maintained below 15%. This means that the dose enhanced for adipose tissue, for example, may vary in the range 6.5% ± 1%. The preventive analysis should be employed especially to verify the positioning of the GNP solution injected in the target. Occasionally, in special cases of ion dose releasable

The composition of molecules containing GNP for drug preparation is particularly important for the tissue absorption and for their localization in the cancer cells to be prepared for radiotherapy or for chemo-therapy treatments, as described in the Patent of Foster and collaborators [4]. Another effect increasing significantly the local absorbed dose in the zone where GNP are injected is due to the increment of the electron generation from Au ionization processes and to their local energy release mainly via Bremsstrahlung effect. The amount of electron energy release contributes to the radiation deposited dose at the Bragg peak position with an increment of the order of 1%-3%, as calculated by our preliminary evaluations. Taking into consideration the electron energy release, in some cases, for example for target tissues at low density (mammary gland, bone marrow, skin, skeletal muscle, adipose tissue, …), the insertion of GNP in solution with high concentrations may produce high local Z enrichment with dose enhancement that may arrive at about 10%. The increment may be higher than 10% if there is the possibility to increase the solution concentration temporally, i.e. maintaining the solution only during the ion treatment, for example. From this point of view, further investigations based on biochemistry, biology and medicine should be performed to validate the proposed use of GNP in radiotherapy using ion beams. A statistical analysis of experimental data should be done, for example in vitro test by measuring the real dose given to the target with and without the insertion of GNP should be performed and analyzed statistically to verify the potential improvement that can be transferred to the in vivo case. Thus GNPs have many attractive physical properties indicating their potentiality to be used in cancer therapy. Their submicrometric size permits the penetration in many organs of the body through the blood and the Enhanced Permeability and Retention (EPR) effect. GNP can chemically bind many molecules, proteins and drugs that can be employed to accumulate high concentration at the tumor sites. At high concentration GNP can be toxic and the concentration used in this investigation, of about 100 mg/cm3, can be considered


near to the maximum value acceptable by in vivo systems. They may induce resonant absorption effects when exposed to the light of specific wavelength, producing heat and local temperature increment that can be used for tumor-selective photothermal therapy. Thus hyperthermia induced by laser, as an example, can be jointed to hadrontherapy, which leads to enhance the absorption of energy loss released along the ion tracks. This article is in agreement with the Krishnan S and collaborators patent [22], which describe a method for the design, manufacturing, and use of a high-Z particle to enhance the effects of ionizing radiation. In particular, the use of a targeting molecule to enable cellular uptake by the target cells (tumor cells or endothelial cells proximate to the tumor) will enhance the dose effect. Many questions need to be answered before GNP complexes enter in the routine clinical use. The factors that affect GNP pharmacokinetics, biodistribution and in vivo toxicity need to be clarified. Of course, long-term investigations are required before use GNPs in the clinical field because for its introduction in the human body and for its permanence for days and/or months, it will be preliminary essential to evaluate their real biocompatibility, the minimum level of toxicity, and the mutagenic potential of the GNP uptake. In this direction the patent of Jahnen-Dechent and coworkers [23] indicates that the gold nanocluster compounds, especially gold nanoparticles, have a reduced toxicity, especially cytotoxicity. The toxicity can be reduced through chemical processing inducing stability, for example using Au-S chemical bonding or ligand based on organic thiols, dithiols, disulfides, and others, becoming the preparate appropriate for be used in medical diagnostics and therapy. In conclusion, the concept of using GNPs for radiation therapy can be studied by SRIM Code simulation but also by other Monte Carlo and GEANT simulations [24, 25]. Although the enhancement of radiation dose in tumors loaded with high-Z materials have been attempted for several decades, the emergence of new GNP with high biocompatible characteristics and high absorption energy has motivated scientists to investigate their applications in conjunction with radiation therapy that can enhance the dose deposition in tumors. There are controversial results about the impact of radiation energy and GNP size in recently published articles [15]. To optimize the technique of GNP-based radiation therapy for clinical application, some studies should be carried out to address the effect of photon, electron and ion energy and GNP size separately. A work is in progress to evaluate the released dose as a function of the GNP size and to evaluate the statistical analysis of presented data considering tissues with specific gradients in density and GNP concentration. Also, more biological experiments on cell lines are required to clarify the observed differences in dose enhancement effect and enhancement impact of cell type in GNP-based radiation therapy.


laboratories of Physics and Chemistry. The nanoparticles concentration, the chemical bond of nanoparticles to specific carrier molecules or proteins, the kind of used solvent, the particles dimensions and shapes are actually well controllable and reproducible with high precision. Less investigated, for moment, are the methods to inject the solution in the different biological tissues, interfaces and organs in which cancer cells are present. The injection can be localized or diffused, depending on the extended volume of the cancer region. Moreover it is predictable that the introduction of the solution containing GNP may be diffused more or less quickly from the point of introduction, depending on the physiological presence of liquids, on the nature of tissues and interfaces and on the organ functionality. Thus in many cases may be that immediately after the GNP injection the radiotherapy must be performed. Many of these aspects must be investigated in vitro in biochemistry laboratories in order to known as the GNP uptake and decay acts for different biological environments where it can be injected. From the point of view of radiotherapy the data discussed in this article should be confirmed with spatial dose measurements in phantoms simulating the irradiated region of the treated human body, both for superficial and depth zones, and as the method may afflict the nearest healthy tissues. The future developments will use certainly these methods of tissue enrichment with nanoparticles enhancing the locally released dose especially in protontherapy where the GNP localization can be reached by the Bragg peak. However all the above discussed aspects need to be further investigated before gold nanoparticles enhancing protontherapy efficiency may be really employed on the man for a sure win in the fight against cancer. CONFLICT OF INTEREST The authors confirm that this article content has no conflicts of interest. ACKNOWLEDGEMENTS The author wishes to thank the Physics Department of Messina University and the INFN-Laboratori Nazionali del Sud of Catania per their scientific support given to these researches. REFERENCES [1] [2] [3] [4] [5]

5. CURRENT AND FUTURE DEVELOPMENTS Nowadays the use of biocompatible solutions containing Au nanoparticles represents a step easily realizable in many

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