Monte Carlo Simulation Study on Dose Enhancement by Gold Nanoparticles in Brachytherapy

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1 Journal of the Korean Physical Society, Vol. 56, No. 6, June 2010, pp Monte Carlo Simulation Study on Dose Enhancement by Gold Nanoparticles in Brachytherapy Sungkoo Cho, Jong Hwi Jeong and Chan Hyeong Kim Department of Nuclear Engineering, Hanyang University, Seoul Myonggeun Yoon Proton Therapy Center, National Cancer Center, Goyang-si (Received 28 January 2010, in final form 9 April 2010) Radiation dose enhancement by injection of a high atomic number (Z) material into tumor volumes has been studied for various radiation sources and different concentrations of gold nanoparticles. Brachytherapy employs low energy photons of less than 0.5 MeV, which indeed is the optimal energy range for radiation dose enhancement by introduction of high-z material. The present study uses the MCNPX T M code to estimate the dose enhancement by gold nanoparticles for the four common brachytherapy sources ( 137 Cs, 192 Ir, 125 I, and 103 Pd). Additionally, cisplatin (H 6Cl 2N 2Pt), a platinum-based chemotherapeutic drug, was used to evaluate the dose enhancement. The simulated source models were evaluated with reference to the calculated TG-43 parameter values. The dose enhancement in the tumor region due to the gold nanoparticles and cisplatin was evaluated according to the dose enhancement factor (DEF). The maximum values of the average DEFs were found to be 1.03, 1.11, 3.43, and 2.17 for the 137 Cs, 192 Ir, 125 I, and 103 Pd sources, respectively. The dose enhancement values for the low-energy sources were significantly higher than those for the high-energy sources. The dose enhancement due to cisplatin was calculated by using the same approach and was found to be comparable to that of the gold nanoparticles. The maximum value of the average DEF for cisplatin was 1.12 for the 5% concentration level in water and a 192 Ir source. We confirmed that cisplatin could be applied to cancer therapy that combines chemotherapeutic drugs with radiation therapy. The results presented herein will be used to study dose enhancement in tumor regions using various radiation modalities with high atomic number materials. PACS numbers: Lq, Wz, Jw Keywords: Monte Carlo, Dose enhancement, Gold nanoparticle, Brachytherapy, MCNPX, Cisplatin DOI: /jkps I. INTRODUCTION The object of radiotherapy is to concentrate adequate radiation doses within tumor volumes without damaging normal tissue. However, tumor cells that are radioresistant are difficult to remove completely by radiotherapy, in that the radiation modalities use only limited doses to minimize the radiation effect on the normal tissue surrounding the targeted region and the path of the irradiated beam [1]. In order to circumvent this problem, the injection of high- atomic number (Z) material into tumors has been studied, and the development of radiosensitizers and radioprotectors to improve the effect of radiotherapy has been explored [1]. Injecting high-z material into tumor volumes can enhance doses in photon beam therapy, an approach studied initially about 50 years ago [2 7]. Recently, Hainfeld et al. successfully re- radioyoon@gmail.com; Fax: moved a tumor from a mouse by using gold nanoparticles with 250-kVp X-ray beams [8]. Such dose enhancements have been calculated with Monte Carlo simulation codes for various radiation sources and gold nanoparticle concentrations. Cho [9] estimated the dose enhancements by gold nanoparticles for various external photon beams. Zhang et al. [10] calculated the same for an 192 Ir source. Although many studies were carried out for dose enhancement due to nanoparticles, most radiation sources in previous studies such as 250-kVp, megavoltage photon beam are either too low in energy, which can t be used in a clinic or too high in energy, which doesn t show significant dose enhancement. Unlike the X-ray radiotherapy, brachytherapy, which entails low-energy photons ( 500 kev) is considered to be one of the most effective modalities in radiotherapy for high Z material injection. Although dose enhancement by an 192 Ir source has been studied before, the energy level of Ir-192 which ranges from to 1.06 MeV does not represent the energy of

2 Monte Carlo Simulation Study on Dose Enhancement by Gold Nanoparticles in Brachytherapy Sungkoo Cho et al conventional brachytherapy sources. For example, the average photon energies of 125 I and 103 Pd, which are widely used as permanent implants, are and MeV, respectively. These values are roughly an order of magnitude lower than the average energy of 192 Ir. As Dose enhancement in materials is mainly caused by the photoelectric effect, the dose enhancement depends on the energy of the radiation source and might be significantly different for various sources, depending on their energies. Therefore, it is important to evaluate quantitatively the dose enhancement by nanoparticles in lowenergy brachytherapy sources ( 125 I and 103 Pd) used to treat cancer in radiation therapy. Another issue in the study of dose enhancement factors using nanoparticles is how one can actually deliver the nanoparticles near the tumor. This is a very important issue because without delivery of the nanoparticles to the tumor, dose enhancement due to the nanoparticles is meaningless. Cisplatin is a platinum-based chemotherapy drug used to treat various types of cancers, including sarcomas, some carcinomas, lymphomas, and germ cell tumors. It is known that cisplatin attaches to and can be inserted into a tumor where it kills cancer cells. Therefore, the study of dose enhancement by cisplatin can be very important in the sense that it may suggest a possible solution for nanoparticle delivery to a tumor. In addition, it may also suggest that all the drugs containing high-z elements can be utilized as radio-sensitizers in cancer therapy. The objective of the present study was to estimate, through Monte Carlo simulation studies and for various brachytherapy sources, the degrees of dose enhancement in tumor volumes due to gold nanoparticles. Additionally, cisplatin (H 6 Cl 2 N 2 Pt) was tested in place of gold nanoparticles to determine the possibility of simultaneous treatment with chemotherapy and radiotherapy. Fig. 1. Schematic drawings of (a) the EZIP Cs-137, (b) the BEBIG Ir-192, (c) the I-125 (Saxena et al.), and (d) the MED3633 Pd-103 brachytherapy sources. II. METHODS AND MATERIALS The four radionuclides normally used in brachytherapy were selected to evaluate the dose enhancements by gold nanoparticles. Table 1 lists the physical characteristics and source models of each radionuclide. The structures and dimensions of each source model are illustrated in Fig. 1. The EZIP Cs-137 tube source model is composed of a cesium-oxide ceramic rod (density: 1.47 g/cm 3 ) and stainless steel capsules (density: 7.9 g/cm 3 ). The capsules are divided on 304 stainless steel tubes of mm inner-wall and 0.33 mm outer-wall thicknesses. There is a 0.09 mm air gap between the inner- and the outer-wall of the stainless steel capsules. The BEBIG Ir-192 HDR source model [10] is composed of an Ir-192 core and a stainless- steel capsule (density: 8.02 g/cm 3 ). The cylindrical source core is 3.5 mm long 0.6 mm in diameter, and the capsule is 5.18 mm long Fig. 2. Monte Carlo simulation animation view of (a) the tissue phantom case and (b) the gold-tissue mixture case. 1 mm in diameter. The wire, 40 mm long 1 mm in diameter, is made of the same metal as the capsule. The I-125 seed source model developed by Saxena et al. [11] includes I-125 adsorbed on palladium-coated silver spheres of 0.5 mm in diameter. The capsule is titanium (density: g/cm 3 ) of 4.75 mm in length and 0.8 mm in diameter. The MED 3633 Pd-103 source model [12] is composed of 4 Pd seeds, 2 gold/copper alloy markers, and a titanium capsule (density: g/cm 3 ). The Pd seeds and markers are spheres of 0.5 mm in diameter, and the capsule size is 4.5 mm long 0.8 mm in diameter. The dimensions of the steel wire are 3.0 mm long 0.8 mm in diameter. In this study, a spherical phantom of 40 mm in radius

3 Journal of the Korean Physical Society, Vol. 56, No. 6, June 2010 Table 1. Physical characteristics and source models of radionuclides used in brachytherapy. Radionuclide Half-life Photon energy (MeV) Source model 137 Cs 30.0 yr EZIP Cs Ir 73.8 days (0.38 avg.) BEBIG Ir I 59.4 days avg. I-125 (Saxena) 103 Pd 17.0 days avg. MED 3633 Pd-103 Fig. 3. Chemical structure of cisplatin. filled with four-component tissue of ICRU 44 [13] was used for the Monte Carlo calculations. The tumor was defined as a cube (10 mm 10 mm 10 mm) of goldtissue mixture and was located 15 mm from the origin of the spherical phantom (Fig. 2). The concentration levels of the gold nanoparticles in the tumor cube were 7, 18, and 30 mg Au/g, the same as the values used in previous studies by Hainfeld et al. [8] and Cho [9]. Additionally, cisplatin (H 6 Cl 2 N 2 Pt) was substituted for the gold nanoparticles in the case of the 192 Ir source case and were tested under the same conditions. Cisplatin is a platinum-based chemotherapeutic drug, and the chemical structure of cisplatin is shown in Fig. 3. The concentration levels of cisplatin in the tumor region were 1%, 3%, and 5% in water. The TG-43 parameters [14] (i.e., the dose-rate constant and the radial dose function) were calculated by means of the Monte Carlo code to evaluate the simulated source models and were compared with previous data [15]. The dose-rate constant, which varies with the radionuclide and the source model, was defined as the ratio of the dose rate at the reference point (r 0 = 1 cm, θ 0 = 90 ) to the air-kerma strength. The dose-rate and the air-kerma strength were calculated with the Monte Carlo code by utilizing the approach of Zhang et al. [10] and Williamson [16]. The dose-rate constant was calculated according to the dose rate and the air-kerma strength in a 0.1 mm diameter sphere located at 0.5 cm, 1.0 cm, 1.5 cm, and 2.0 cm on the y-axis. The uncertainties of the air-kerma strength were less than 1.0% in the Monte Carlo calculation. The radial dose function, which is defined as the dose fall-off on the transverse plane due to photon scattering and attenuation, was calculated under the same calculation conditions. Fig. 4. Dose-rate constant and radial dose function for a brachytherapy source. The Monte Carlo calculations were performed with the MCNPX T M code. The cross-section data of this study were acquired using that code s default values [17]. A beam parallel to the y-axis and based on each source construction was used to reduce the calculation time and elevate the interaction efficiency. The tracklength estimator of the MCNPX T M [17], F6 tally, was used to calculate the doses deposited at 2-35 mm distances on the y-axis. The statistical uncertainty was less than 3%. III. RESULTS The AAPM TG-43 parameters were calculated using the MCNPX T M code to evaluate the simulated source models. Both the dose-rate constants and the radial dose functions were calculated at 4 points (r = 0.5 cm, 1.0 cm, 1.5 cm, and 2.0 cm) along the y-axis, as shown in Fig 4. The radial dose function of each model was normalized to the reference point (r = 1.0 cm). The parameters of the 103 Pd model, as compared with the findings for the other source models, show the differences caused by the markers in the source construction. Subsequently, the TG-43 dose parameter values for the 192 Ir source model were compared with the data of Granero et al. [14], as shown in Table 2. The percentile difference in dose-rate constant between this study and that of Granero et al. was less than 5%. The maximum percentile difference in the radial dose function under the same conditions was 1.2% at r = 1.5 cm. The TG-43 parameter values for the 192 Ir source model agreed with the findings of Granero et al. Source model doses for depths ranging from 2 mm to 35 mm (y-axis) were also calculated using the

4 Monte Carlo Simulation Study on Dose Enhancement by Gold Nanoparticles in Brachytherapy Sungkoo Cho et al Table 2. TG-43 dose parameter values for the Ir-192 brachytherapy source. Dose rate constant Radial dose function Y (cm) This study Granero et al. % difference This study Granero et al. % difference Table 3. Average dose enhancement factor (DEF) for a brachytherapy source. Concentration 137 Cs 192 Ir 125 I 103 Pd 7 mg mg mg distribution of the dose enhancement factors for cisplatin is shown in Fig 6. The average DEFs were 1.03, 1.07, and 1.12 for 1%, 3%, and 5% concentrations in water, respectively. These results are encouraging because they show that cisplatin can be applied to cancer therapy that combines a chemotherapeutic drug with radiation therapy. IV. CONCLUSION MCNPX T M code. The dose enhancement factor (DEF), defined by Cho [9] as the ratio of the dose with and without gold nanoparticles in the tumor region, was used to evaluate the dose enhancement of gold nanoparticles. The average DEF-to-tumor-volume ratios are listed in Table 3. The dose in the tumor region increased with increasing concentration of gold nanoparticles. The maximum values of the average DEFs were 1.03, 1.11, 3.43, and 2.17 for the 137 Cs, 192 Ir, 125 I, and 103 Pd sources, respectively. The dose enhancement values for the 125 I and the 103 Pd sources were significantly higher than those for the 137 Cs and 192 Ir high-dose-rate (HDR) sources because the photoelectric absorption coefficients of gold at the K- (80.7 kev), L- ( kev), and M-edge ( kev) are high. Hainfeld et al. [1] reported that the optimal energy of the dose enhancement due to gold is about 20 kev. Moreover, the photon energy (21 kev) of the 103 Pd source is similar to the optimal energy. However, the DEFs for the 103 Pd source were lower than those for the 125 I source because when most of the energy was lost the incident photons of the former source penetrated through the tissue phantom in front of the tumor region. Figure 5 shows the DEF distribution for the source models and gold concentrations. While the DEF distributions for the 137 Cs and the 192 Ir sources were entirely uniform in the tumor, the effect is very heterogeneous in the tumor region for the 125 I and the 103 Pd sources. The physical reasons for this heterogeneity may be the high scattering effects of low-energy photon beam, which results in a significant fluence reduction as photons enter the nanopartcle-induced tumor. This result suggests that one must be careful when applying nanopartilces with the 125 I and the 103 Pd sources. The dose enhancement by the cisplatin, additionally, was calculated for the 192 Ir source by using the same approach as was used with the gold nanoparticles. The This study conducted Monte Carlo simulations to estimate the degree of tumor-volume dose enhancement due to gold nanoparticles and cisplatin for the four common brachytherapy sources. Source models of the four radionuclides typically used in brachytherapy were precisely simulated by means of the MCNPX T M code, and the TG-43 parameters were calculated. The dose enhancements in tumor regions injected with gold nanoparticles and cisplatin were evaluated by using the dose enhancement factor (DEF). The maximum value of the average DEFs was 3.43 for a 30 mg/g Au concentration level and a 125 I source, reflecting the fact that the interactions probability of the photoelectric effect is high at lower energies. The dose enhancement due to cisplatin for a 192 Ir source was as high as that of the gold nanoparticles. Thus, we confirmed that cisplatin can be utilized in cancer therapy combining a chemotherapeutic drug with radiation therapy. Although these results can be directly applied to study dose enhancement in tumor regions, the more refined Monte Carlo method using adequate modeling of nanomparcles and physical experiment using scintillating detectors is called for in future studies. ACKNOWLEDGMENTS This work was supported by a research grant from the National Cancer Center, Korea (no ). This work was also supported by Korean Ministry of Knowledge Economy (2008-P-EP-HM-E )/Sunkwang Atomic Energy Safety co., Ltd and the Nuclear R&D Program in Korea through PEFP. REFERENCES

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