|Ahead of print publication
Measurement of dose enhancement factor for Xoft Axxent electronic brachytherapy device using nanoparticle-embedded alginate film and radiochromic film
Nitin R Kakade1, Abhishek Das2, Rajesh Kumar1, SD Sharma1, Nandita Maiti2, Ridhima Chadha2, BK Sapra1
1 Radiological Physics & Advisory Division, Bhabha Atomic Research Centre; Homi Bhabha National Institute, Anushaktinagar, Mumbai, India
2 Homi Bhabha National Institute, Anushaktinagar; Radiation &Photochemistry Division, Bhabha Atomic Research Centre, Mumbai, India
|Date of Submission||04-Feb-2020|
|Date of Acceptance||12-Mar-2021|
|Date of Web Publication||02-Jun-2021|
Nitin R Kakade,
Radiological Physics & Advisory Division, Bhabha Atomic Research Centre; Homi Bhabha National Institute, Anushaktinagar, Mumbai
Source of Support: None, Conflict of Interest: None
Aim: Inw nanoparticles-aided radiotherapy, the radiation sensitivity of tumor is increased with the infusion of nanoparticles in tumor. This therapeutic modality is capable of delivering enhanced dose to tumor, without exceeding the normal tissue tolerance dose. Further, the quantification of the enhanced dose using suitable dosimeter is important. The present study is aimed at measuring the dose enhancement factors (DEFs) using the combination of nanoparticles-embedded alginate (Alg) film and unlaminated Gafchromic EBT3 film.
Materials and Methods: Gold nanoparticles (AuNPs)- and silver nanoparticles (AgNPs)-embedded Alg polymer films were synthesized and characterized using standard techniques. Further, a customized version of the Gafchromic EBT3 film, i.e., unlaminated EBT3 film, was specially fabricated. The DEFs were measured using Xoft Axxent electronic brachytherapy device.
Results: The surface plasmon resonance (SPR) and particle size of AuNPs were found to be 550 and 15 ± 2 nm, respectively. In the case of AgNPs, the SPR and particle size were recorded as 400 and 13 ± 2 nm, respectively. The DEFs measured, using unlaminated EBT3 film, for Xoft Axxent electronic brachytherapy using AuNPs and AgNPs were 1.35 ± 0.02 and 1.20 ± 0.01, respectively.
Conclusion: The increase in dose enhancement during nanoparticles-aided electronic brachytherapy can be attributed to dominance of photoelectric effect, due to the presence of low-energy X-rays. The investigation indicates that the Xoft Axxent electronic brachytherapy device is suitable for nanoparticles-aided brachytherapy.
Keywords: Dose enhancement, electronic brachytherapy, Gafchromic film, nanoparticles
|How to cite this URL:|
Kakade NR, Das A, Kumar R, Sharma S D, Maiti N, Chadha R, Sapra B K. Measurement of dose enhancement factor for Xoft Axxent electronic brachytherapy device using nanoparticle-embedded alginate film and radiochromic film. J Can Res Ther [Epub ahead of print] [cited 2021 Jun 22]. Available from: https://www.cancerjournal.net/preprintarticle.asp?id=317457
| > Introduction|| |
In the last few decades, the use of high atomic number nanoparticles as a radiation dose enhancer in the treatment of cancer has been studied in great extent. The inbuilt mechanisms of leaky vasculature possessed by tumor cells are used advantageously for enhanced permeability and retention (EPR). The EPR phenomenon and the biocompatible formulations of nanoparticles have supported to develop the therapeutic technique of infusing nanoparticles inside the tumor. The tumor region infused with nanoparticles is relatively more radiation sensitive compared to tumor region without nanoparticles. Basically, the dose enhancement in the tumor region is because of the enhanced photoelectric effect, which depends on the atomic number of nanoparticles and photon energy. Importantly, the photoelectric effect is inversely proportional to photon energy, and hence, the degree of the dose enhancement is dependent on the energy of the photon used in the treatment. The outcome of dose enhancement studies involving phantoms, cell culture, and Monte Carlo simulations demonstrates that the low-energy kilo-voltage (kV) photons are advantageous in comparison to the high-energy megavoltage photons to achieve higher dose enhancement.,,,,
The dose enhancement in tumor infused with nanoparticles was coined as a dose enhancement factor (DEF) and is expressed as the ratio of the dose absorbed in the tumor region with and without the presence of nanoparticles. The dose enhancement is significant for low photon energies and the higher dose enhancement was observed in the energy range of 20–100 keV. Both brachytherapy methods, e.g., radioisotope-based brachytherapy and electronic brachytherapy, use radiation sources of this energy range. In addition, reported optimal energy to get the highest DEFs for gold and silver was 40–45 and 30–35 keV, respectively. Various authors have studied dose enhancement in tumor infused with gold nanoparticles (AuNPs) using low-energy gamma-emitting brachytherapy sources (103Pd, 125I, 131Cs, 169Yb, and 170Tm).,,, However, most of these sources are low-dose rate and limited to temporary brachytherapy implants. Further, the commonly used high-dose rate (HDR) 192Ir brachytherapy source was found incompatible for nanoparticles-aided brachytherapy., These observations motivated to explore the outcome of nanoparticles-aided treatment via electronic brachytherapy.
In the recent era, electronic brachytherapy using a miniaturized X-ray source is being used clinically. An electronic brachytherapy device uses miniaturized X-ray tube operated at voltages in the range of 50–70 kVp. The low kV electronic brachytherapy sources of different makes and models are available commercially from Etseya, Xoft Axxent, and Intrabeam. Among these, Xoft Axxent is the popularly used system for HDR brachytherapy treatments, specifically in the case of cervix, vagina, and breast. Xoft Axxent devices contain X-ray source operated at 50 kVp with an average X-ray energy of 28.8 keV. The dose fall-off characteristic of Xoft device is similar to those of the low-energy isotopes used in brachytherapy, yet it has HDR property similar to that of the 192Ir brachytherapy source. The use of Xoft Axxent device for nanoparticles-aided brachytherapy is of interest due to the average X-ray energy being closer to the optimal energy for dose enhancement. This makes Xoft Axxent device a suitable for nanoparticles-aided electronic brachytherapy.
Cho et al. computed the DEFs for 125I, 169Yb, and 50 kVp X-rays for AuNPs-assisted brachytherapy using Monte Carlo methods and demonstrated that tumor dose enhancement of the order of 40% could be achieved using 50 kVp X-rays. Shahhoseini et al. determined the dose enhancement due to AuNPs in lung and prostate cancer cells with Xoft Axxent device. The DEFs in the lung and prostate cancer cells were 2.06 and 2.90, respectively, when the cells were incubated with 1 mM (2% w/w) AuNPs concentration. Cifter et al. calculated the DEFs for different tumor sizes irradiated with 50 kVp Xoft Axxent device at 1 cm away from the lumpectomy cavity. An analytic calculation methodology was adapted, and a clinically significant DEF of 1.20 was recorded. Further, they have proposed to incorporate AuNPs into a micrometer (μm) thick polymer film on the surface of lumpectomy balloon applicator and irradiate the tumor using 50 kVp Xoft Axxent device. The findings and proposal of Cifter et al. motivated us for synthesizing AuNPs- and AgNPs-embedded alginate (AuNPs-Alg and AgNPs-Alg) polymer film. It was thought that the combination of nanoparticles-embedded Alg film and unlaminated Gafchromic EBT3 film can help in experimental measurements of the DEFs.
Most of the studies conducted to quantify the DEFs using Xoft Axxent electronic brachytherapy system are either Monte Carlo or cell culture based. To the best of our knowledge, the experimental measurement of the DEFs using AuNPs-Alg and AgNPs-Alg film for Xoft Axxent electronic brachytherapy device is yet to be investigated. The main aim of this study was to determine experimentally the DEFs for Xoft Axxent system using in-house–developed AuNPs-Alg and AgNPs-Alg film.
| > Material and MethodS|| |
Synthesis of gold nanoparticles- and silver nanoparticles-embedded alginate films
For synthesis of AgNPs, precursor chemicals, e.g., sodium alginate, silver nitrate (AgNO3, 99.0%), polyvinyl pyrrolidone (PVP, 40,000 MW), and calcium nitrate (CaNO3, 99.0%), were purchased from Merck (Kenilworth, NJ, USA). Alg-capped AgNPs were synthesized using chemical reduction method. Initially, the reduction of 20 mM AgNO3 solution was carried out in the presence of 1% (w/v) sodium alginate solution. The alkaline condition (pH = 10) and temperature (60°C) were maintained during the synthesis procedure. The homogeneous viscous solution of AgNPs in Alg polymer was prepared by adding 2 ml of 20 mM stock solution to a mixture of 2% sodium alginate solution (7 ml) and 8% PVP solution (1 ml). Finally, AgNPs-Alg films were prepared from this homogenous solution. The dried AgNPs-Alg films were cross-linked using 0.5 M CaNO3 solution and were used for dosimetric experiments.
AuNPs-Alg films were synthesized following the method described by Das et al. In summary, 2% sodium alginate solution was dried, and then, it is cross-linked in a 0.5 M CaNO3 solution. Then, this dried solution was immersed in 3 mM HAuCl4 solution (1 ml) for sufficient time, e.g., 1 day, to complete the gold uptake procedure. Finally, AuNPs-Alg films were prepared and reduced by 0.05 M D-glucose solution (5 ml) and used in dosimetric study. The concentration of AuNPs and AgNPs present in the Alg polymer was 0.4% (w/w).
In addition, the Alg film not containing nanoparticles was also synthesized for dosimetric comparison. Ten pieces of AuNPs-Alg, AgNPs-Alg, and Alg films of dimension 1 cm × 1 cm were prepared from the same batch and used in characterization and dosimetric part. During synthesis, care was taken to keep the thickness of AuNPs-Alg, AgNPs-Alg, and Alg films similar to minimize their impact on dose enhancement analysis. [Figure 1] shows the photograph of AgNPs-Alg film (left) and AuNPs-Alg film (right).
|Figure 1: Photograph showing pieces of silver nanoparticles-embedded alginate film (left) and gold nanoparticles-embedded alginate film (right)|
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The UV-vis absorption spectroscopy is the most fundamental, yet reliable technique, which gives a direct understanding of nanoparticles' shape and size. The formation of nanoparticles was monitored by observing changes in the color of the solution, during the synthesis stage. Further, the quantitative analysis was carried out using UV-vis absorption spectroscopy of the homogeneous solution of AuNPs and AgNPs in Alg polymer, using JASCO V-650 spectrophotometer.
The particle size of AuNPs and AgNPs present in the Alg polymer was determined using atomic force microscopy (AFM) (A100 instrument, A.P.E. Research, Italy). For this, uncross-linked nanoparticles-embedded Alg films, both AuNPs-Alg and AgNPs-Alg films, were dissolved in 3 ml water. On dissolution, released AuNPs and AgNPs were spin-coated on the respective mica sheet and AFM measurements were carried out. A data analysis software, Gwyddion software (Czech Metrology Institute, Brno, Czech Republic), was used for visualization and data analysis of AFM images. The average particle size of AuNPs and AgNPs was calculated from AFM images obtained after triplicate measurements.
The thickness of AuNPs-Alg, AgNPs-Alg, and Alg films of dimension 1 cm × 1 cm was measured using a precision thickness gauge (Hanatek made). However, the films having similar thicknesses were selected for dosimetric measurements.
Xoft Axxent electronic brachytherapy system
The portable Xoft Axxent electronic brachytherapy system (Ms XOFT, a subsidiary of iCAD, USA) comprises a miniature X-ray tube, a controller, a cooling tube, and a set of applicators. The supply of high voltage and filament current to X-ray source is given through the controller, which also helps in circulating cooling water to X-ray source. The X-ray tube is 2.25 mm in diameter and 5.4 mm in length. The operating voltage and currents are 50 kV and 300 μA. Further, it is equipped with an inbuilt electrometer and a well-type ionization chamber. The dosimeter assembly verifies the output of the unit before the treatment. [Figure 2] shows Xoft Axxent electronic brachytherapy system used in this work.
The dose fall-off characteristic of X-rays matches with the characteristics of the low-energy isotopic sources used in brachytherapy. In addition, the dose rate of Xoft Axxent X-ray source is comparable to the dose rate of 192Ir HDR brachytherapy source. Hence, it is a kind of HDR equipment and used clinically for treating cancers of cervix and vagina.
Measurement of dose enhancement factors
The laminated Gafchromic EBT3 film (International Specialty Products, Wayne, NJ, USA) is made up of radiation-sensitive active emulsion layer (28 μm thick) sandwiched between two polyester substrates, each of thickness 125 μm. However, the laminated film finds limited application because that the dose enhancement effect is due to the generation of low-range photoelectrons and Auger electrons in the immediate vicinity of nanoparticles. Hence, a customized version of the Gafchromic EBT3 film was specially fabricated by removing one of the polyester substrates, and it was referred as unlaminated Gafchromic EBT3 film. The schematic structural details of the unlaminated Gafchromic EBT3 film are shown in [Figure 3].
|Figure 3: Schematic structural details of unlaminated Gafchromic EBT3 film|
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The dosimetric measurements were carried out with Xoft Axxent device for both AuNPs and AgNPs. About 4 cm × 4 cm sample of the Gafchromic film was fixed on a solid water phantom, and AuNPs-Alg and AgNPs-Alg pieces (approximately 1 cm × 1 cm) were placed in direct contact with the radiation-sensitive side of the Gafchromic film. Nanoparticles-patched Gafchromic film sample was then irradiated with a dose of 2 Gy. This set of experiment was repeated by irradiating the Gafchromic film with Alg patch only. In addition, the similar experiment was repeated using laminated Gafchromic EBT3 films. All the measurements were repeated three times. [Figure 4] shows the experimental setup to irradiate unlaminated Gafchromic film in the presence of AuNPs-Alg and AgNPs-Alg film.
|Figure 4: Photograph of the experimental setup to irradiate unlaminated Gafchromic film in presence of gold nanoparticles-embedded alginate (or silver nanoparticles-embedded alginate) film|
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The irradiated films were kept in light-free environment for 48 h to complete the polymerization process and then scanned using a flatbed scanner (Epson Expression 10000XL, EPSON UK). Standard scanning protocol was followed by acquiring images in transmission mode with films placed in landscape orientation. 72 dot per inch corresponding to a pixel size of 0.35 mm × 0.35 mm was selected for scanning, and red channels of scanned films were analyzed using the ImageJ Software (U. S. National Institutes of Health, Bethesda, Maryland, USA). The change in color density of exposed film was recorded in terms of net optical density (NOD) using the following formula,
where PVun and PVex are the pixel values of the control film (i.e., unexposed film) and the exposed film, respectively. The DEF, a ratio of NOD with AgNPs-Alg (or AuNPs-Alg) and NOD with only Alg film, was determined.
| > Results|| |
The results of UV-vis absorption spectrometry of AuNPs and AgNPs show the surface plasmon resonance (SPR) absorption peak at 550 and 400 nm, respectively. UV-vis spectroscopy is an exceptionally valuable technique for the characterization of synthesized nanoparticles. In general, SPR peak is an unique characteristics of each nanoparticles. The appearance of SPR peak at 550 nm is considered as a confirmation test for the presence of AuNPs in the synthesized film. In the similar manner, SPR peak at 400 nm confirms the formation of AgNPs. [Figure 5]a and [Figure 5]b shows the UV-vis absorption spectrum of AuNPs and AgNPs, respectively.
|Figure 5: (a) UV-vis spectrum of gold nanoparticles present in 1 cm × 1 cm gold nanoparticles-embedded alginate film. (b) UV-vis spectrum of silver nanoparticles present in 1 cm × 1 cm silver nanoparticles-embedded alginate film|
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AFM images of AuNPs and AgNPs obtained from AuNPs-Alg film and AgNPs-Alg film are shown in [Figure 6]a and [Figure 6]b, respectively. The average particle size of AuNPs and AgNPs was found to be 15 ± 2 and 13 ± 2 nm, respectively.
|Figure 6: (a) Atomic force microscopy image of gold nanoparticles obtained from gold nanoparticles-embedded alginate film. (b) Atomic force microscopy image of silver nanoparticles obtained from silver nanoparticles-embedded alginate film|
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All the films, e.g., AuNPs-Alg, AgNPs-Alg, and Alg films having a similar thickness, were selected from the same lot, and the thickness was found to be 100 ± 2 μm. The DEFs measured, using unlaminated Gafchromic EBT3 film, for Xoft Axxent electronic brachytherapy system with AuNPs and AgNPs were 1.35 ± 0.02 and 1.20 ± 0.01, respectively. However, the measurement using laminated Gafchromic EBT3 film does not show any dose enhancement.
| > Discussion|| |
AuNPs and AgNPs synthesis method implemented in this work was very simple, easy to implement, and inexpensive. Both nanoparticles were synthesized in the Alg polymer. Alg is biocompatible in nature and plays a dual role in synthesis procedure. It not only is used as a reducing agent but also acts as a capping agent to nanoparticles. Moreover, it was observed that a thin layer of calcium alginate is present over nanoparticles, which would shield nanoparticles from direct contact with tissue. Most of the in vitro and in vivo studies reported the effect of nanoparticles size on uptake of nanoparticles within cells and their impact on radiation dose enhancement. One group of studies concludes that 50 nm as the optimal particle size for higher radiation dose enhancement. However, the second group suggests 12–27 nm size as an optimal size. The work of Sonavane et al. and Zhang et al. indicates that the smaller nanoparticles move through the body more easily, and hence, they are not as toxic as slightly larger nanoparticles. Owing to these observations, the particle size of nanoparticles used in this work was maintained in the range of 12–27 nm.
The DEFs calculated using the theoretical approach lead to the conclusion that the dose enhancement caused by the inclusion of high Z nanoparticles into a tumor is energy dependent and hence more important in the kV energy range. It is reported that the clinically, significant dose enhancement is observed for photon energy up to 300 keV. Further, HDR brachytherapy using 192Ir radioisotope is not suitable for nanoparticles-aided brachytherapy., However, in future, a potential radioisotope such as 170Tm (Eavg: 66 keV) and 169Yb (Eavg: 93 keV) which are thought to be used in HDR brachytherapy can be useful in nanoparticles-aided brachytherapy, owing to their lower photon energies.
Furthermore, among the available kV-based therapeutic modalities, Xoft Axxent was in clinical use and thought to be a suitable candidate for nanoparticles-aided brachytherapy. The important advantage of electronic brachytherapy is rapid dose fall-off which is well suited to deliver less radiation dose to healthy tissue and organs near the tumor boundary. As it is an isotope-free treatment modality, the chances of off-condition leakage and generation of radioactive waste are very minimal. This is a low kVp electronic brachytherapy device and hence, delivers relatively less radiation exposure to operational personnel. Apart from the listed advantages, the main feature is the average X-ray energy being closer to the optimal energy required for the highest dose enhancement for both AuNPs and AgNPs. Further, due to the HDR application, absence of emergency situation, e.g., source struck case, and longer lifetime (~700 min), this device can be preferred in radiation oncology departments.
As far as the dose enhancement is concerned, Moradi et al. estimated the DEFs using AuNPs in Intrabeam brachytherapy (mean energy between 27.8 and 29 keV) using MCNPX Monte Carlo method. The macroscopic DEF of 1.30 was recorded at 1 cm from the surface of 1.5 cm spherical applicator for 5 mg/g (0.5% weight fraction) concentration of AuNPs in water. Cho et al. computed DEFs for tumor loaded with 7 mg gold g −1 and the DEF of 1.57 was recorded at 1 cm from the center of 50 kVp X-ray source. In the study conducted by Cifter et al., 50 kVp Xoft devices were simulated using Monte Carlo method and the DEF of 1.20 was estimated at 1 cm away from the lumpectomy cavity. Guidelli and Baffa reported the experimental results of DEFs in alanine dosimeters several concentrations of AgNPs using electron spin resonance spectroscopy. A Siemens clinical Ortho-voltage unit operating at 80 kV X-ray beam (effective energy 30 keV) was used for irradiation purpose, and the DEF of 1.36 was measured for an alanine dosimeters containing 0.5% AgNPs of size 280 nm. We have observed DEF of 1.20 ± 0.01 with AgNPs. However, the DEF of 1.35 ± 0.02 was noticed for AuNPs. The differences in DEFs can be attributed to the difference in concentration, the size of nanoparticles, the experimental setup, and the approach of the study, e.g., experimental versus simulation. This work also compares AuNPs and AgNPs with respect to the dose enhancement. The DEFs due to gold was found to be higher than silver, and these results are consistent with theoretical findings. The DEFs were shown to be concentration dependent also. The DEFs achievable by AuNPs can be obtained by increasing the concentration of AgNPs. The biocompatibility of AgNPs is studied in the literature, and hence being relatively less costly, AgNPs also can be good choice for nanoparticles-assisted electronic brachytherapy.
Concerning the dosimetric measurements, a feasibility of polymer gels and Fricke dosimeters for DEFs measurement was studied extensively. A homogeneous solution of nanoparticles was added in polymer gel and Fricke dosimeters to quantify the DEFs. However, these dosimeters are mostly used in research laboratories, and their use in routine clinical dosimetry is very laborious, time-consuming, and limited. Hence, the synthesized AuNPs-Alg and AgNPs-Alg films can serve the purpose of dosimetric measurement using film dosimeter, which is most routinely used in radiotherapy departments. The measurement using laminated films was able to quantify the dose enhancements. However, the measurement using laminated film does not show any dose enhancement. This is due to the presence of polyester substrate, which prevents the low-range photoelectrons and Auger electrons reaching the sensitive part of the film. The results of the study indicate that the idea of removing the polyester substrate, as in the case of unlaminated Gafchromic film, is useful. Hence, the combination of unlaminated film and nanoparticles-embedded Alg film can be used for the measurement of dose enhancement in nanoparticles-aided electronic brachytherapy.
| > Conclusion|| |
The DEFs were measured for Xoft Axxent electronic brachytherapy system using AuNPs-Alg and AgNPs-Alg film. Alg, a biocompatible material, was used in the synthesis of nanoparticles. The experimental measurements were conducted using a combination of unlaminated Gafchromic EBT3 film and nanoparticles-embedded Alg film. The investigation indicates that Xoft Axxent electronic brachytherapy device is suitable for nanoparticles-aided electronic brachytherapy.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]