Influence of photon beam energy on the dose enhancement factor caused by gold and silver nanoparticles: An experimental approach Eder José Guidelli and Oswaldo Baffa Citation: Medical Physics 41, 032101 (2014); doi: 10.1118/1.4865809 View online: http://dx.doi.org/10.1118/1.4865809 View Table of Contents: http://scitation.aip.org/content/aapm/journal/medphys/41/3?ver=pdfcov Published by the American Association of Physicists in Medicine Articles you may be interested in Investigation of the effects of cell model and subcellular location of gold nanoparticles on nuclear dose enhancement factors using Monte Carlo simulation Med. Phys. 40, 114101 (2013); 10.1118/1.4823787 Radiosensitizing effect of gold nanoparticles in carbon ion irradiation of human cervical cancer cells AIP Conf. Proc. 1530, 205 (2013); 10.1063/1.4812924 Monte Carlo investigation of the increased radiation deposition due to gold nanoparticles using kilovoltage and megavoltage photons in a 3D randomized cell model Med. Phys. 40, 071710 (2013); 10.1118/1.4808150 Comment on “Enhanced relative biological effectiveness of proton radiotherapy in tumor cells with internalized gold nanoparticles” [Appl. Phys. Lett. 98, 193702 (2011)] Appl. Phys. Lett. 100, 026101 (2012); 10.1063/1.3675570 Enhanced relative biological effectiveness of proton radiotherapy in tumor cells with internalized gold nanoparticles Appl. Phys. Lett. 98, 193702 (2011); 10.1063/1.3589914
Influence of photon beam energy on the dose enhancement factor caused by gold and silver nanoparticles: An experimental approach Eder José Guidellia) and Oswaldo Baffa Departamento de Física, Faculdade de Filosofia, Ciências e Letras de Ribeirão Preto, Universidade de São Paulo, Av. Bandeirantes, 3900, 14040-901 Ribeirão Preto, SP, Brazil
(Received 9 June 2013; revised 30 December 2013; accepted for publication 2 February 2014; published 21 February 2014) Purpose: Noble metal nanoparticles have found several medical applications in the areas of radiation detection; x-ray contrast agents and cancer radiation therapy. Based on computational methods, many papers have reported the nanoparticle effect on the dose deposition in the surrounding medium. Here the authors report experimental results on how silver and gold nanoparticles affect the dose deposition in alanine dosimeters containing several concentrations of silver and gold nanoparticles, for five different beam energies, using electron spin resonance spectroscopy (ESR). Methods: The authors produced alanine dosimeters containing several mass percentage of silver and gold nanoparticles. Nanoparticle sizes were measured by dynamic light scattering and by transmission electron microscopy. The authors determined the dose enhancement factor (DEF) theoretically, using a widely accepted method, and experimentally, using ESR spectroscopy. Results: The DEF is governed by nanoparticle concentration, size, and position in the alanine matrix. Samples containing gold nanoparticles afford a DEF higher than 1.0, because gold nanoparticle size is homogeneous for all gold concentrations utilized. For samples containing silver particles, the silver mass percentage governs the nanoparticles size, which, in turns, modifies nanoparticle position in the alanine dosimeters. In this sense, DEF decreases for dosimeters containing large and segregated particles. The influence of nanoparticle size-position is more noticeable for dosimeters irradiated with higher beam energies, and dosimeters containing large and segregated particles become less sensitive than pure alanine (DEF < 1). Conclusions: ESR dosimetry gives the DEF in a medium containing metal nanoparticles, although particle concentration, size, and position are closely related in the system. Because this is also the case as in many real systems of materials containing inorganic nanoparticles, ESR is a valuable tool for investigating DEF. Moreover, these results alert to the importance of controlling the sizeposition of nanoparticles to enhance DEF. © 2014 American Association of Physicists in Medicine. [http://dx.doi.org/10.1118/1.4865809] Key words: alanine, silver, gold, electron spin resonance, radiation therapy, dosimetry 1. INTRODUCTION Researchers have added atoms with high atomic number to target materials, to increase their ionizing radiation absorption.1 This method enhances the sensitivity of radiation detectors and dosimeters,2–5 increases contrast in x-ray images, and improves the efficacy of cancer radiation therapy.6 In this context, nanoparticles consisting of high-atomicnumber atoms have emerged as a new tool to overcome inhomogeneity issues in the case of radiation detectors7, 8 and to facilitate the delivery and uptake of such nanoparticles by tumor cells.9 Energy absorption by matter is governed by the mass absorption coefficient, which increases as the atomic number of the material augments.10 Therefore, incorporating highatomic-number particles into a given material raises its mass absorption coefficient, which can be calculated by the Bragg rule for compounds and mixtures when taking the weight fractions of each atom into account.10 Although this method is largely used to estimate the mass absorption coefficient of composite materials, it does not consider inhomogeneities in
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the medium, i.e., the composite is always considered to have homogeneously distributed atoms. Hence, many discrepancies between the theoretical and experimental results arise.7, 11 In this sense, many papers have reported how particle size influences dose deposition in the medium around a nanoparticle using computation methods.12 The experimental evaluation of the dose enhancement caused by metal nanoparticles has been performed by in vitro experiments, various radical probes, and DNA plasmid systems.13–20 It is also noteworthy that the nanoparticles size, concentration, and position are closely related in real systems of materials containing inorganic nanoparticles.11, 21, 22 In this sense, nanoparticles concentration usually dictates their size, which in turns, modifies their position in the host medium.11, 21, 22 Therefore, all these parameters (concentration, size, and position), and not only the size, should be taken into account to determine dose enhancement caused by the nanoparticles. To evaluate how the high-atomic-number nanoparticles affects the dose deposition in the host medium by an experimental approach, the electron spin resonance (ESR) or electron magnetic resonance (EMR) spectroscopy is an interesting
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E. J. Guidelli and O. Baffa: Influence of photon beam energy on the dose enhancement factor
strategy. This dosimetric technique is unique because it only accounts for the dosimetric properties of the metal nanoparticles in the surrounding dosimetric medium. The optical properties of metal nanoparticles can affect other dosimetric modalities, such as thermoluminescence or optically stimulated luminescence, quenching or enhancing luminescence,23 in such a way that one cannot accurately assess the dosimetric properties. There are many dosimetric materials available for ESR dosimetry purposes, such as alanine, 2-methyl-alanine, sucrose, lithium formate, etc. Although alanine has a decreased sensitivity to photons with energies below 100 keV,24, 25 so that caution must be taken under irradiation with low energies, it is a dosimetric standard compound because it offers signal stability after irradiation, linear response, and tissue equivalence to photons with energy above 100 keV.24 Interaction between ionizing radiation and the alanine molecules produces free radicals26 that ESR spectroscopy can detect. The most stable alanine radical named R1 radical originates from deamination of the alanine molecule (CH3 CHCOOH). The hyperfine interactions of the unpaired electron with four hydrogen atoms lead to a characteristic ESR spectrum for the alanine radiation-induced free radical consisting of five lines which intensity follows a 1:4:6:4:1 ratio.24 In fact, a total of three radicals (R1, R2, and R3) compose the total ESR spectrum of alanine, but R1 contributes the most to the central ESR line.27 The intensity of the spectrum is proportional to the amount of free radicals present in the exposed sample and to the incident radiation dose.24 Thus, for dosimetric purposes, the peak-topeak amplitude of the central line of the ESR spectrum is employed. This paper investigates how silver and gold nanoparticles affect the dose deposition in alanine at different energies. To this end, we prepared samples of alanine containing several mass percentage of gold and silver nanoparticles, and applied them as radiation dosimeters as monitored by ESR. We measured nanoparticle size by dynamic light scattering (DLS); determined their position using transmission electron microscopy; and calculated the dose enhancement factor theoretically and experimentally. We discuss the agreement and discrepancies between theory and our results on the basis of the nanoparticle concentration, size, and position, as well as the photon beam energy. The results can be important for both dosimetric and radiation therapy purposes.
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2.A.1. Silver nanocomposites preparation
Silver nanoparticles were produced as reported in Ref. 7. Briefly, a 2 mmol l−1 AgNO3 aqueous solution was added to a freshly prepared 4 mmol l−1 NaBH4 aqueous solution. The color of the system became immediately bright yellow, indicating the formation of a colloidal dispersion. Average sizes of the silver nanoparticles present in the as prepared colloidal dispersion were estimated by the DLS technique, which gave a mean size of 30 nm. Thereafter, a 1.1 mol l−1 DL-alanine aqueous solution was employed as dispersant in different proportions, in such a way that the mass percentage of silver in the dried nanocomposites varied from 0.01% to 10%. Samples were dried in an oven, at a temperature of 40 ◦ C, and labeled according to mass percentage in the dried nanocomposites. For example, the nanocomposite prepared with Ag 0.01% w/w was named 0.01%NpAg, and so on, up to the sample 10%NpAg. Particle size was also measured for the silver/alanine nanocomposites, revealing that the nanoparticle size depends on the quantity of silver in the alanine matrix: samples containing from 0.01% to 0.1% silver display average particle size of 30 nm (similar to the as prepared silver nanoparticles); the sample 0.5%NpAg has average particle size of 280 nm; and the samples 1%NpAg up to 10%NpAg display particles larger than 1 μm (Fig. 1). 2.A.2. Gold nanocomposites preparation
Gold nanoparticles were synthesized as follows: a 2 mmol l−1 HAuCl4 aqueous solution was added to a freshly prepared 8 mmol l−1 NaBH4 aqueous solution, under vigorous stirring. DLS technique measurements indicated that the gold nanoparticles had a mean size of 5 ± 2 nm. Thereafter, different volumes of 1.1 mol l−1 alanine aqueous solution were added to the gold nanoparticles dispersion. The gold mass percentage in the nanocomposites ranged from 0.01% to 3%. The gold nanoparticles were very stable in the alanine medium in such a way that even the gold/alanine nanocomposites containing a high amount of gold nanoparticles present constant nanoparticle size (Fig. 1). The dispersions were dried in an oven, at a temperature of 40 ◦ C, yielding the powdered nanocomposites. Samples were labeled according to the mass percentage of gold in the dried nanocomposites. For instance, the nanocomposite prepared with Au 0.01% w/w was named 0.01%NpAu, and so on, up to the sample 3%NpAu.
2. MATERIALS AND METHODS 2.A. Nanocomposites preparation
2.B. Characterization techniques
The chemicals employed in the experiments were analytical reagent grade and used as received. Silver nitrate (99.8%) was provided by Cennabras, chloroauric acid (HAuCl4 ) (99.999%) was provided by Sigma-Aldrich, sodium borohydride (NaBH4 ) was purchased from Sigma, and DLalanine (99%) was obtained from Acros Organics. All the aqueous solutions were prepared with purified Milli-QTM water.
The average particle size was obtained by the DLS technique, with the aid of a Zeta-Sizer system (Malvern Instruments), at a fixed wavelength (633 nm He-Ne laser) and angle (90◦ ). Nanoparticle size, morphology, and position were investigated on a JEOL-JEM-100 CXII transmission electron microscope (TEM), by drying a drop of the colloidal dispersions on a copper grid covered with a conductive polymer. Powdered samples (≈30 mg) were placed into
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F IG . 1. (a) Particle size obtained by DLS for silver and gold composites, and TEM images from samples 1%NpAu (b), 0.01%NpAg (c), and 3%NpAg (d). The inset in (a) corresponds to a zoom in the low metal concentration region.
cylindrical capsules measuring 1.0 × 0.5 cm and irradiated with different energies. The delivered dose was 5 Gy for all the energies tested. Radiation beam specifications are published in Ref. 25. A Siemens Stabilipan II clinical orthovoltage unit was employed for the 80, 120, 180, and 200 kV x-ray beams. The effective energies of the x-ray beams were 30, 40, 90, and 107 keV, respectively, as calculated by the half value layer (HVL). Aluminum filters were used for the 80 and 120 kV; and copper filters were employed for the 120 and 200 kV. A field size of 8 × 10 cm2 and a 40 cm source-todosimeter distance with no build-up cap was used. To satisfy backscattering conditions, capsules were placed above a 10 cm acrylic layer. For the 60 Co irradiation, a Siemens Gammatron S-80 was employed, with a source-to-dosimeter distance of 80 cm, a field size of 15 × 15 cm2 , and a 0.5 cm acrylic layer placed over the capsules as a build-up cap. ESR measurements were obtained for the irradiated powders at room temperature, on a JEOL-JES-FA 200 (9.5 GHz) spectrometer. Irradiated samples of pure DL-alanine and the different nanocomposites (≈30 mg) were placed into a quartz tube positioned in the center of a JEOL cylindrical cavity. This quantity (30 mg) corresponds to a maximum height of 1 cm inside the quartz tube, thus ensuring that the whole sample is within the active volume of the ESR cavity. Routine measurements of the Mn2+ standard were performed to correct for possible response variations. The parameters employed for the ESR measurements were: microwave power = 5 mW, central field = 338.5 mT, sweep width = 10 mT, sweep time = 1 min, modulated amplitude = 0.4 mT, amplifier gain = 3000×, time constant = 0.3 s, and a total of five scans (sweeps) for signal averaging in each sample. The total mass of each sample, i.e., mass of alanine + mass metal nanoparticles, was used to normalize the respective spectrum. Medical Physics, Vol. 41, No. 3, March 2014
The increased sensitivity in the case of alanine dosimeters containing metal nanoparticles is proportional to the increase in the dose delivered to the sample, due to the presence of metal nanoparticles with high atomic number. The experimental sensitivity gain for the nanocomposites, or the dose enhancement factor (DEF), was obtained by the peak-to-peak amplitude of the central line of the normalized ESR spectra of the sample containing silver nanoparticles divided by the peak-to-peak amplitude of the central line of the normalized ESR spectra of pure DL-alanine. The theoretical DEF values were calculated as the ratio between the mass absorption coefficients of the nanocomposites by the mass absorption coefficient of pure alanine, as used by many other authors:28–30 μen ρ
Nc,hv DEF ≈ μen , ρ
(1)
ala,hv
where (μen /μ)hν is the radiation mass absorption coefficient for photons with a given energy hν and the subscripts Nc and ala account for nanocomposite and pure alanine, respectively. The expected mass absorption coefficients for the ionizing radiation were obtained from the National Institute of Standards and Technology– (NIST), “Physical Reference Data” data base.31 It is noteworthy that the theoretical DEF as calculated above presupposes that the samples are exposed to a monochromatic x-ray. However, samples were irradiated with polychromatic x-ray beams, so, the effective energy of the beams was employed to calculate the theoretical DEF. Once this method does not account for the real spectrum of photon energies when calculating the delivered dose, its use was limited to the unique purpose of predicting the behavior of the DEF as a function of the mass percentage of the metal in
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the nanocomposites (if linear or exponential, for example), to compare and act as a reference for the experimental results. 3. RESULTS AND DISCUSSION Figure 1(a) summarizes the gold and silver nanoparticle size as a function of the mass percentage of the respective metal. The gold nanoparticle size does not vary in the gold/alanine nanocomposites (∼5 nm). However, the silver nanoparticles size grows with the silver content. Transmission electron microscopy images confirmed that particles are spherical, well dispersed, and stable in size for all the gold/alanine nanocomposites and for the silver/alanine nanocomposites with a silver mass percentage below 0.5% [Figs. 1(b) and 1(c)]. For higher silver mass percentage, TEM images reveled that the growth pointed by DLS is caused by nanoparticles agglomeration, and agglomerates of up 4 μm can be observed [Fig. 1(d)]. Also, Fig. 1(d) reveals that the large silver clusters become segregated from the alanine matrix.7, 8 The large size of agglomerates depicted by TEM (4 μm) compared to the size revealed by DLS (1.5 μm) may be due to agglomeration during the drying procedure. Figures 2(a) and 2(b) depict the theoretical DEF of the nanocomposites as a function of the gold and silver mass percentage, respectively, for five beam energies employed herein. As the amount of gold and silver increases in the nanocomposite, the DEF rises linearly. This happens because the mass absorption coefficient of the gold and silver atoms is larger than that of alanine, raising the amount of energy transferred to the medium and consequently enhancing the production of free radicals. When the x-ray beam energy increases, the mass absorption coefficient of gold and silver decreases, reducing the DEF. This result is in agreement with results obtained by other authors using Monte Carlo simulation.12, 32 This implies that the dosimetric response of the nanocomposites strongly depends on energy. It is noteworthy that DEF factor is higher for the 40-keV beam energy than for the 30-keV one in case of silver/alanine
samples; for gold/alanine composites, the DEF is similar at these two energy values. Although the mass absorption coefficients of gold and silver diminishes upon increasing energy, in the specific 30–40 keV energy range the mass absorption coefficient of alanine decreases more abruptly than the mass absorption coefficients of these metals. For example, the mass absorption coefficient of silver decreases from 1.660 × 10+1 to 9.869 × 10+0 in the 30–40 keV energy range, while the mass absorption coefficient of alanine decreases from 1.076 × 10−1 to 5.034 × 10−2 . Because the mass absorption coefficient of alanine is the dividend of the ratio, this abrupt reduction in its value increases the DEF, despite the lower mass absorption coefficient of the metal guest. The experimental results reveal that increasing the photon energy lowers the DEF, as shown by the inset in Fig. 3, agreeing with the theoretical prediction. However, the experimental curve of DEF as a function of the gold mass percentage is not linear (Fig. 3). The theoretical prediction as calculated from Eq. (1) gives the total dose delivered to the sample, i.e., the dose that both alanine and metal nanoparticles absorb, whereas ESR is only sensitive to the dose delivered to the alanine molecules, i.e., the total dose minus the dose delivered to the metal nanoparticles. As the gold mass percentage rises, the dose delivered to the alanine molecules increases, but the portion of the dose that is self-absorbed by the gold nanoparticles also augments. Therefore, the DEF increases with rising gold mass percentage nonlinearly (Fig. 3). Hence, care must be taken when using the prediction employed here and by other authors,28–30 mainly for systems containing a high load of metal nanoparticles: the theoretical prediction does not take the contribution of the self-absorbed dose into account. Such miscalculation could have serious consequences for patients undergoing cancer radiation therapy using these metal nanoparticles, although most clinical studies have considered relatively low nanoparticle concentrations (
Influence of photon beam energy on the dose enhancement factor caused by gold and silver nanoparticles: An experimental approach Eder José Guidellia) and Oswaldo Baffa Departamento de Física, Faculdade de Filosofia, Ciências e Letras de Ribeirão Preto, Universidade de São Paulo, Av. Bandeirantes, 3900, 14040-901 Ribeirão Preto, SP, Brazil
(Received 9 June 2013; revised 30 December 2013; accepted for publication 2 February 2014; published 21 February 2014) Purpose: Noble metal nanoparticles have found several medical applications in the areas of radiation detection; x-ray contrast agents and cancer radiation therapy. Based on computational methods, many papers have reported the nanoparticle effect on the dose deposition in the surrounding medium. Here the authors report experimental results on how silver and gold nanoparticles affect the dose deposition in alanine dosimeters containing several concentrations of silver and gold nanoparticles, for five different beam energies, using electron spin resonance spectroscopy (ESR). Methods: The authors produced alanine dosimeters containing several mass percentage of silver and gold nanoparticles. Nanoparticle sizes were measured by dynamic light scattering and by transmission electron microscopy. The authors determined the dose enhancement factor (DEF) theoretically, using a widely accepted method, and experimentally, using ESR spectroscopy. Results: The DEF is governed by nanoparticle concentration, size, and position in the alanine matrix. Samples containing gold nanoparticles afford a DEF higher than 1.0, because gold nanoparticle size is homogeneous for all gold concentrations utilized. For samples containing silver particles, the silver mass percentage governs the nanoparticles size, which, in turns, modifies nanoparticle position in the alanine dosimeters. In this sense, DEF decreases for dosimeters containing large and segregated particles. The influence of nanoparticle size-position is more noticeable for dosimeters irradiated with higher beam energies, and dosimeters containing large and segregated particles become less sensitive than pure alanine (DEF < 1). Conclusions: ESR dosimetry gives the DEF in a medium containing metal nanoparticles, although particle concentration, size, and position are closely related in the system. Because this is also the case as in many real systems of materials containing inorganic nanoparticles, ESR is a valuable tool for investigating DEF. Moreover, these results alert to the importance of controlling the sizeposition of nanoparticles to enhance DEF. © 2014 American Association of Physicists in Medicine. [http://dx.doi.org/10.1118/1.4865809] Key words: alanine, silver, gold, electron spin resonance, radiation therapy, dosimetry 1. INTRODUCTION Researchers have added atoms with high atomic number to target materials, to increase their ionizing radiation absorption.1 This method enhances the sensitivity of radiation detectors and dosimeters,2–5 increases contrast in x-ray images, and improves the efficacy of cancer radiation therapy.6 In this context, nanoparticles consisting of high-atomicnumber atoms have emerged as a new tool to overcome inhomogeneity issues in the case of radiation detectors7, 8 and to facilitate the delivery and uptake of such nanoparticles by tumor cells.9 Energy absorption by matter is governed by the mass absorption coefficient, which increases as the atomic number of the material augments.10 Therefore, incorporating highatomic-number particles into a given material raises its mass absorption coefficient, which can be calculated by the Bragg rule for compounds and mixtures when taking the weight fractions of each atom into account.10 Although this method is largely used to estimate the mass absorption coefficient of composite materials, it does not consider inhomogeneities in
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the medium, i.e., the composite is always considered to have homogeneously distributed atoms. Hence, many discrepancies between the theoretical and experimental results arise.7, 11 In this sense, many papers have reported how particle size influences dose deposition in the medium around a nanoparticle using computation methods.12 The experimental evaluation of the dose enhancement caused by metal nanoparticles has been performed by in vitro experiments, various radical probes, and DNA plasmid systems.13–20 It is also noteworthy that the nanoparticles size, concentration, and position are closely related in real systems of materials containing inorganic nanoparticles.11, 21, 22 In this sense, nanoparticles concentration usually dictates their size, which in turns, modifies their position in the host medium.11, 21, 22 Therefore, all these parameters (concentration, size, and position), and not only the size, should be taken into account to determine dose enhancement caused by the nanoparticles. To evaluate how the high-atomic-number nanoparticles affects the dose deposition in the host medium by an experimental approach, the electron spin resonance (ESR) or electron magnetic resonance (EMR) spectroscopy is an interesting
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E. J. Guidelli and O. Baffa: Influence of photon beam energy on the dose enhancement factor
strategy. This dosimetric technique is unique because it only accounts for the dosimetric properties of the metal nanoparticles in the surrounding dosimetric medium. The optical properties of metal nanoparticles can affect other dosimetric modalities, such as thermoluminescence or optically stimulated luminescence, quenching or enhancing luminescence,23 in such a way that one cannot accurately assess the dosimetric properties. There are many dosimetric materials available for ESR dosimetry purposes, such as alanine, 2-methyl-alanine, sucrose, lithium formate, etc. Although alanine has a decreased sensitivity to photons with energies below 100 keV,24, 25 so that caution must be taken under irradiation with low energies, it is a dosimetric standard compound because it offers signal stability after irradiation, linear response, and tissue equivalence to photons with energy above 100 keV.24 Interaction between ionizing radiation and the alanine molecules produces free radicals26 that ESR spectroscopy can detect. The most stable alanine radical named R1 radical originates from deamination of the alanine molecule (CH3 CHCOOH). The hyperfine interactions of the unpaired electron with four hydrogen atoms lead to a characteristic ESR spectrum for the alanine radiation-induced free radical consisting of five lines which intensity follows a 1:4:6:4:1 ratio.24 In fact, a total of three radicals (R1, R2, and R3) compose the total ESR spectrum of alanine, but R1 contributes the most to the central ESR line.27 The intensity of the spectrum is proportional to the amount of free radicals present in the exposed sample and to the incident radiation dose.24 Thus, for dosimetric purposes, the peak-topeak amplitude of the central line of the ESR spectrum is employed. This paper investigates how silver and gold nanoparticles affect the dose deposition in alanine at different energies. To this end, we prepared samples of alanine containing several mass percentage of gold and silver nanoparticles, and applied them as radiation dosimeters as monitored by ESR. We measured nanoparticle size by dynamic light scattering (DLS); determined their position using transmission electron microscopy; and calculated the dose enhancement factor theoretically and experimentally. We discuss the agreement and discrepancies between theory and our results on the basis of the nanoparticle concentration, size, and position, as well as the photon beam energy. The results can be important for both dosimetric and radiation therapy purposes.
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2.A.1. Silver nanocomposites preparation
Silver nanoparticles were produced as reported in Ref. 7. Briefly, a 2 mmol l−1 AgNO3 aqueous solution was added to a freshly prepared 4 mmol l−1 NaBH4 aqueous solution. The color of the system became immediately bright yellow, indicating the formation of a colloidal dispersion. Average sizes of the silver nanoparticles present in the as prepared colloidal dispersion were estimated by the DLS technique, which gave a mean size of 30 nm. Thereafter, a 1.1 mol l−1 DL-alanine aqueous solution was employed as dispersant in different proportions, in such a way that the mass percentage of silver in the dried nanocomposites varied from 0.01% to 10%. Samples were dried in an oven, at a temperature of 40 ◦ C, and labeled according to mass percentage in the dried nanocomposites. For example, the nanocomposite prepared with Ag 0.01% w/w was named 0.01%NpAg, and so on, up to the sample 10%NpAg. Particle size was also measured for the silver/alanine nanocomposites, revealing that the nanoparticle size depends on the quantity of silver in the alanine matrix: samples containing from 0.01% to 0.1% silver display average particle size of 30 nm (similar to the as prepared silver nanoparticles); the sample 0.5%NpAg has average particle size of 280 nm; and the samples 1%NpAg up to 10%NpAg display particles larger than 1 μm (Fig. 1). 2.A.2. Gold nanocomposites preparation
Gold nanoparticles were synthesized as follows: a 2 mmol l−1 HAuCl4 aqueous solution was added to a freshly prepared 8 mmol l−1 NaBH4 aqueous solution, under vigorous stirring. DLS technique measurements indicated that the gold nanoparticles had a mean size of 5 ± 2 nm. Thereafter, different volumes of 1.1 mol l−1 alanine aqueous solution were added to the gold nanoparticles dispersion. The gold mass percentage in the nanocomposites ranged from 0.01% to 3%. The gold nanoparticles were very stable in the alanine medium in such a way that even the gold/alanine nanocomposites containing a high amount of gold nanoparticles present constant nanoparticle size (Fig. 1). The dispersions were dried in an oven, at a temperature of 40 ◦ C, yielding the powdered nanocomposites. Samples were labeled according to the mass percentage of gold in the dried nanocomposites. For instance, the nanocomposite prepared with Au 0.01% w/w was named 0.01%NpAu, and so on, up to the sample 3%NpAu.
2. MATERIALS AND METHODS 2.A. Nanocomposites preparation
2.B. Characterization techniques
The chemicals employed in the experiments were analytical reagent grade and used as received. Silver nitrate (99.8%) was provided by Cennabras, chloroauric acid (HAuCl4 ) (99.999%) was provided by Sigma-Aldrich, sodium borohydride (NaBH4 ) was purchased from Sigma, and DLalanine (99%) was obtained from Acros Organics. All the aqueous solutions were prepared with purified Milli-QTM water.
The average particle size was obtained by the DLS technique, with the aid of a Zeta-Sizer system (Malvern Instruments), at a fixed wavelength (633 nm He-Ne laser) and angle (90◦ ). Nanoparticle size, morphology, and position were investigated on a JEOL-JEM-100 CXII transmission electron microscope (TEM), by drying a drop of the colloidal dispersions on a copper grid covered with a conductive polymer. Powdered samples (≈30 mg) were placed into
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F IG . 1. (a) Particle size obtained by DLS for silver and gold composites, and TEM images from samples 1%NpAu (b), 0.01%NpAg (c), and 3%NpAg (d). The inset in (a) corresponds to a zoom in the low metal concentration region.
cylindrical capsules measuring 1.0 × 0.5 cm and irradiated with different energies. The delivered dose was 5 Gy for all the energies tested. Radiation beam specifications are published in Ref. 25. A Siemens Stabilipan II clinical orthovoltage unit was employed for the 80, 120, 180, and 200 kV x-ray beams. The effective energies of the x-ray beams were 30, 40, 90, and 107 keV, respectively, as calculated by the half value layer (HVL). Aluminum filters were used for the 80 and 120 kV; and copper filters were employed for the 120 and 200 kV. A field size of 8 × 10 cm2 and a 40 cm source-todosimeter distance with no build-up cap was used. To satisfy backscattering conditions, capsules were placed above a 10 cm acrylic layer. For the 60 Co irradiation, a Siemens Gammatron S-80 was employed, with a source-to-dosimeter distance of 80 cm, a field size of 15 × 15 cm2 , and a 0.5 cm acrylic layer placed over the capsules as a build-up cap. ESR measurements were obtained for the irradiated powders at room temperature, on a JEOL-JES-FA 200 (9.5 GHz) spectrometer. Irradiated samples of pure DL-alanine and the different nanocomposites (≈30 mg) were placed into a quartz tube positioned in the center of a JEOL cylindrical cavity. This quantity (30 mg) corresponds to a maximum height of 1 cm inside the quartz tube, thus ensuring that the whole sample is within the active volume of the ESR cavity. Routine measurements of the Mn2+ standard were performed to correct for possible response variations. The parameters employed for the ESR measurements were: microwave power = 5 mW, central field = 338.5 mT, sweep width = 10 mT, sweep time = 1 min, modulated amplitude = 0.4 mT, amplifier gain = 3000×, time constant = 0.3 s, and a total of five scans (sweeps) for signal averaging in each sample. The total mass of each sample, i.e., mass of alanine + mass metal nanoparticles, was used to normalize the respective spectrum. Medical Physics, Vol. 41, No. 3, March 2014
The increased sensitivity in the case of alanine dosimeters containing metal nanoparticles is proportional to the increase in the dose delivered to the sample, due to the presence of metal nanoparticles with high atomic number. The experimental sensitivity gain for the nanocomposites, or the dose enhancement factor (DEF), was obtained by the peak-to-peak amplitude of the central line of the normalized ESR spectra of the sample containing silver nanoparticles divided by the peak-to-peak amplitude of the central line of the normalized ESR spectra of pure DL-alanine. The theoretical DEF values were calculated as the ratio between the mass absorption coefficients of the nanocomposites by the mass absorption coefficient of pure alanine, as used by many other authors:28–30 μen ρ
Nc,hv DEF ≈ μen , ρ
(1)
ala,hv
where (μen /μ)hν is the radiation mass absorption coefficient for photons with a given energy hν and the subscripts Nc and ala account for nanocomposite and pure alanine, respectively. The expected mass absorption coefficients for the ionizing radiation were obtained from the National Institute of Standards and Technology– (NIST), “Physical Reference Data” data base.31 It is noteworthy that the theoretical DEF as calculated above presupposes that the samples are exposed to a monochromatic x-ray. However, samples were irradiated with polychromatic x-ray beams, so, the effective energy of the beams was employed to calculate the theoretical DEF. Once this method does not account for the real spectrum of photon energies when calculating the delivered dose, its use was limited to the unique purpose of predicting the behavior of the DEF as a function of the mass percentage of the metal in
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E. J. Guidelli and O. Baffa: Influence of photon beam energy on the dose enhancement factor
the nanocomposites (if linear or exponential, for example), to compare and act as a reference for the experimental results. 3. RESULTS AND DISCUSSION Figure 1(a) summarizes the gold and silver nanoparticle size as a function of the mass percentage of the respective metal. The gold nanoparticle size does not vary in the gold/alanine nanocomposites (∼5 nm). However, the silver nanoparticles size grows with the silver content. Transmission electron microscopy images confirmed that particles are spherical, well dispersed, and stable in size for all the gold/alanine nanocomposites and for the silver/alanine nanocomposites with a silver mass percentage below 0.5% [Figs. 1(b) and 1(c)]. For higher silver mass percentage, TEM images reveled that the growth pointed by DLS is caused by nanoparticles agglomeration, and agglomerates of up 4 μm can be observed [Fig. 1(d)]. Also, Fig. 1(d) reveals that the large silver clusters become segregated from the alanine matrix.7, 8 The large size of agglomerates depicted by TEM (4 μm) compared to the size revealed by DLS (1.5 μm) may be due to agglomeration during the drying procedure. Figures 2(a) and 2(b) depict the theoretical DEF of the nanocomposites as a function of the gold and silver mass percentage, respectively, for five beam energies employed herein. As the amount of gold and silver increases in the nanocomposite, the DEF rises linearly. This happens because the mass absorption coefficient of the gold and silver atoms is larger than that of alanine, raising the amount of energy transferred to the medium and consequently enhancing the production of free radicals. When the x-ray beam energy increases, the mass absorption coefficient of gold and silver decreases, reducing the DEF. This result is in agreement with results obtained by other authors using Monte Carlo simulation.12, 32 This implies that the dosimetric response of the nanocomposites strongly depends on energy. It is noteworthy that DEF factor is higher for the 40-keV beam energy than for the 30-keV one in case of silver/alanine
samples; for gold/alanine composites, the DEF is similar at these two energy values. Although the mass absorption coefficients of gold and silver diminishes upon increasing energy, in the specific 30–40 keV energy range the mass absorption coefficient of alanine decreases more abruptly than the mass absorption coefficients of these metals. For example, the mass absorption coefficient of silver decreases from 1.660 × 10+1 to 9.869 × 10+0 in the 30–40 keV energy range, while the mass absorption coefficient of alanine decreases from 1.076 × 10−1 to 5.034 × 10−2 . Because the mass absorption coefficient of alanine is the dividend of the ratio, this abrupt reduction in its value increases the DEF, despite the lower mass absorption coefficient of the metal guest. The experimental results reveal that increasing the photon energy lowers the DEF, as shown by the inset in Fig. 3, agreeing with the theoretical prediction. However, the experimental curve of DEF as a function of the gold mass percentage is not linear (Fig. 3). The theoretical prediction as calculated from Eq. (1) gives the total dose delivered to the sample, i.e., the dose that both alanine and metal nanoparticles absorb, whereas ESR is only sensitive to the dose delivered to the alanine molecules, i.e., the total dose minus the dose delivered to the metal nanoparticles. As the gold mass percentage rises, the dose delivered to the alanine molecules increases, but the portion of the dose that is self-absorbed by the gold nanoparticles also augments. Therefore, the DEF increases with rising gold mass percentage nonlinearly (Fig. 3). Hence, care must be taken when using the prediction employed here and by other authors,28–30 mainly for systems containing a high load of metal nanoparticles: the theoretical prediction does not take the contribution of the self-absorbed dose into account. Such miscalculation could have serious consequences for patients undergoing cancer radiation therapy using these metal nanoparticles, although most clinical studies have considered relatively low nanoparticle concentrations (
