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Introduction
Cancer incidence and mortality rates are rising globally. As of 2020, an estimated 193 million people were diagnosed with cancer, resulting in about 10 million deaths. By 2040, the number of cancer cases is expected to increase to 284 million [1]. Radiotherapy is one of the most commonly used local treatment methods for malignant tumors. The main goal of radiotherapy is to optimize tumor control while minimizing side effects on the surrounding normal tissues.
Numerous studies have been conducted to enhance the radiotherapy effects by injecting high atomic number materials such as iodine and gadolinium into tumors [2-4]. These substances increased the radiation dose by the photoelectric effect of X-ray photon beams. With advancements in nanotechnology, gold nanoparticles (GNPs) have been investigated for their potential in cancer diagnosis and treatment [5-7]. Due to their stability, ease of preparation, and excellent penetration ability, GNPs have been studied as radiosensitizers [8]. As high atomic number (Z=79) materials, GNPs interact with photons through the photoelectric effect, making them particularly effective for low-energy X-rays and gamma rays [9,10].
The Monte Carlo simulation calculates the interaction of particles with matter, offering highly accurate estimations of radiation dose [11]. It allows for precise modeling of photon and electron transport, low-energy X-ray interactions, and energy deposition at the nanometer scale [12,13]. This research aimed to assess the radiation dose enhancement effect of GNPs in brachytherapy through Monte Carlo simulations.
Iridium-192 (192Ir) is the most frequently used source for high-dose-rate (HDR) brachytherapy and is applied in treating cervical, breast, head neck, and esophageal cancers. Iodine-125 (125I) is mainly used in low-dose-rate (LDR) brachytherapy, particularly for prostate cancer seed implants. Due to their extensive clinical application, these two isotopes were selected for this research.
Materials and Methods
1. Phantom composition
Initially, the depth-dose distribution of 192Ir and 125I was examined in both water and human tissue phantoms without nanoparticles. The tumor and normal tissue phantoms used in the simulation were based on the composition outlined in the International Commission on Radiation Units & Measurement (ICRU) Report 44 (Table 1). The ICRU phantom more accurately reflects the atomic composition and density of human tissues [14]. The tissue phantom had a density of 1 g/cm3, similar to that of water, but with a different atomic composition. For simulations involving GNPs, their mass was added to the tumor phantom.
2. Structure of the radioisotope
The study utilized 192Ir and 125I as radioactive sources. 192Ir is commonly employed in HDR brachytherapy, whereas 125I is used in LDR brachytherapy. Figs. 1 and 2 illustrate the cross-sectional structures of these sources. The energy spectra referenced in TG-43 were used for these brachytherapy sources [14].
3. Monte Carlo simulation and dose enhancement factor
Monte Carlo N-Particle 4C (MCNP 4C) was employed for the simulations [15]. The photon and electron transport modules, along with the F6 tally, were used to calculate radiation doses. The energy cutoff values were 10 keV for photons and 1 keV for electrons in 192Ir brachytherapy, the cutoff was 1 keV for both photons and electrons in 125I brachytherapy.
Radiation dose distributions were calculated for tumors injected with GNPs at concentrations of 0, 7, 18, and 30 mg/g. The radioactive source was positioned at the center of a spherical tumor with a 3.5-cm-radius surrounded by normal tissue (Fig. 3). Radiation dose calculations were conducted using a 90-voxel grid, with each voxel measuring 1×1×1 mm3. The simulation was repeated three times to ensure verification.
The dose enhancement factor (DEF) was calculated as in “equation (1)”.
Results
1. Radiation dose in the water and tissue phantom
Simulations compared the radiation doses in both water and tissue phantoms. The radiation doses in the tissue phantoms were slightly lower than those in the water phantoms, particularly for 192Ir. The results indicated that the dose difference between the water and tissue phantoms was more pronounced for 192Ir than for 125I (Fig. 4), highlighting the importance of using tissue phantoms for accurate simulations. Photon collisions with GNPs induced photoelectric interactions within the tumor, generating secondary electrons [16]. The elemental composition of the tissue phantom affected the transport of these secondary electrons.
2. Radiation dose enhancement by gold nanoparticles
DEF values were determined for 192Ir and 125I in tissue phantoms with GNP concentrations of 7, 18, and 30 mg/g. For 192Ir, the DEF varied from 1.6 to 2.8, depending on the GNP concentrations (Fig. 5). Higher GNP concentrations led to greater dose enhancement, with 30 mg/g showing the most effective dose enhancement.
For 125I, the DEF was less than 1. Beyond 1 cm from the 125I seed, the radiation dose dropped significantly, complicating DEF calculations (Fig. 6). The radial dose of 125I decreases significantly beyond 1 cm due to increased attenuation and scattering [17]. The GNPs situated a few millimeters from the 125I seed might have undergone photoelectric interactions with the photons. As a result, the DEF values beyond 1 cm from the source did not demonstrate significant enhancement.
Discussion
This study utilized Monte Carlo simulations to calculate the radiation dose enhancement effect of GNPs in brachytherapy. The research focused on two commonly used radioactive sources—192Ir (HDR) and 125I (LDR). 192Ir revealed a significant radiation dose enhancement effect with GNPs, with DEF values ranging from 1.6 to 2.8. 125I did not exhibit significant dose enhancement with GNPs because only one seed was placed in the center of the relatively large tumor. These findings are consistent with previous experimental studies [9,18]. The results suggest that GNPs could be particularly beneficial for HDR brachytherapy using 192Ir for treating relatively large tumors. However, further research is needed to determine the optimal nanoparticle concentration for clinical use. In this study with 125I, only one radioactive source was positioned at the tumor’s center. Future simulations with multiple 125I seeds implanted in the tumor should be conducted to more accurately assess the effect of GNPs in LDR brachytherapy.
One of the limitations of this study is the assumption that GNPs are uniformly distributed within the tumor. Keshavarz and Sardari [19] compared the DEF of uniform and nonuniform distributions of GNPs using Monte Carlo simulations. They found that a nonuniform distribution of GNPs can increase the dose, but the DEF was lower than that of a uniform distribution. To effectively utilize GNPs in clinical applications, it is essential to maintain high and uniform concentrations within tumors while minimizing their accumulation in normal tissues. In a real clinical setting, the distribution may be influenced by various physiological factors such as blood flow and tissue permeability. The penetration of nanoparticles into the surrounding normal tissue can decrease the DEF [19]. Further experimental validation is needed to confirm the feasibility of this approach in vivo using animal models.
This study utilized a simple spherical tumor phantom. Future studies should incorporate patient-specific anatomical phantoms derived from computed tomography (CT) images to better mirror real clinical conditions. A recent Monte Carlo study showed that the DEF of GNPs varies depending on the tissue type; bone exhibited the lowest DEF, while adipose tissue had the highest values [20]. A CT-derived patient-specific phantom would aid in predicting the heterogeneous dose distributions in different tissues [21].
For the clinical application of GNPs in brachytherapy, additional preclinical research with animal models is necessary. Recent research involving rabbit retinoblastoma models showed that combining brachytherapy with 125I and hyperthermia with GNPs reduced the relative tumor size [22]. Despite the substantial amount of in vitro and in vivo data, few clinical trials have examined the use of GNPs as radiosensitizers. Toxicity poses a significant challenge in the clinical application of GNPs as radiosensitizers. Intravenously administered GNPs can accumulate in the liver, spleen, or kidneys [23]. Intratumoral injection of GNPs before brachytherapy might reduce the toxicity and deserves further investigation.
A recent Monte Carlo simulation study also investigated the dose enhancement by GNPs for external beam radiotherapy using high-energy X-ray beams (6 MV, 18 MV), where the DEF was found to be approximately 1.02 [24]. In vivo studies that confirm the radiosensitizing effect of GNPs in high-energy X-ray therapy would be clinically valuable.
Additionally, recent studies indicate that the radiosensitizing effect of GNPs is not solely due to physical interactions but also to chemical and biological mechanisms [25]. Combining radiotherapy with GNPs resulted in stronger immunogenic cell death in glioblastoma cells in mice [26]. Research on the radiosensitization effect of GNPs is necessary not only from a physical standpoint but also from biological and immunological perspectives.
Conclusions
The maximum DEF was 2.6 for a 30 mg/g concentration of GNPs in the tumor with an 192Ir source. GNPs could be advantageous in HDR brachytherapy using 192Ir. Future studies with patient-specific phantoms are needed to assess the realistic distribution of GNPs and optimize their concentrations. Additionally, in vivo studies using animal models are necessary to confirm the dose-enhancement effect of GNPs.
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