Dose Enhancement Factor Research Articles

Significant Radiation Enhancement Effects by Gold Nanoparticles in Combination with Cisplatin in Triple Negative Breast Cancer Cells and Tumor Xenografts.

Gold nanoparticles (AuNPs) and cisplatin have been explored in concomitant chemoradiotherapy, wherein they elicit their effects by distinct and overlapping mechanisms. Cisplatin is one of the most frequently utilized radiosensitizers in the clinical setting; however, the therapeutic window of cisplatin-aided chemoradiotherapy is limited by its toxicity. The goal of this study was to determine whether AuNPs contribute to improving the treatment response when combined with fractionated cisplatin-based chemoradiation in both in vitro and in vivo models of triple-negative breast cancer (MDA-MB-231Luc+). Cellular-targeting AuNPs with receptor-mediated endocytosis (AuNP-RME) in vitro at a noncytotoxic concentration (0.5 mg/ml) or cisplatin at IC25 (12 μM) demonstrated dose enhancement factors (DEFs) of 1.25 and 1.14, respectively; the combination of AuNP-RME and cisplatin resulted in a significant DEF of 1.39 in vitro. Transmission electron microscopy (TEM) images showed effective cellular uptake of AuNPs at tumor sites 24 h after intratumoral infusion. Computed tomography (CT) images demonstrated that the intratumoral levels of gold remained stable up to 120 h after infusion. AuNPs (0.5 mg gold per tumor) demonstrated a radiation enhancement effect that was equivalent to three doses of cisplatin at IC25 (4 mg/kg), but did not induce intrinsic toxicity or increased radiotoxicity. Results from this study suggest that AuNPs are the true radiosensitizer in these settings. Importantly, AuNPs enhance the treatment response when combined with cisplatin-based fractionated chemoradiation. This combination of AuNPs and cisplatin provides a promising approach to improving the therapeutic ratio of fractionated radiotherapy.

Radiosensitization of non-small-cell lung cancer cells and xenografts by the interactive effects of pemetrexed and methoxyamine

Background and purposeThe anti-folate pemetrexed is a radiosensitizer. In pre-clinical models, pemetrexed is more effective along with the base-excision-repair inhibitor methoxyamine. We tested whether methoxyamine enhances pemetrexed-mediated radiosensitization of lung adenocarcinoma cells and xenografts. Materials and methodsA549 and H1299 cells were evaluated for cell cycle distribution by flow cytometry, radiosensitization by clonogenic assay, and DNA repair by neutral comet assay and repair protein activation. H460 cells were included in some studies. Xenografts in nude mice received drug(s) and/or radiation, and tumor growth was monitored by caliper and in vivo toxicity by animal weight. ResultsExposure to pemetrexed/methoxyamine for 24 (H1299, H460) or 48 (A549)hours before irradiation resulted in accumulation of cells near the radiosensitive G1/S border; dose-enhancement factors of 1.62±0.19, 1.97±0.25, and 1.67±0.30, respectively; reduction of mean inactivation dose by 32%, 30%, and 46%, respectively; and significant reductions of SF2 and SF4 (p<0.05). Radiosensitization was associated with rapid DNA double-strand-break rejoining and increased levels of DNA–PKcs. Both tumor-growth rate and tumor-growth delay were significantly improved by adding methoxyamine to pemetrexed pre-irradiation (p<0.0001); no mice lost weight during treatment. ConclusionsAddition of methoxyamine to pemetrexed and fractionated radiotherapy may improve outcome for patients with locally advanced non-squamous non-small-cell lung cancer.

Enhancement of radiosensitivity of melanoma cells by pegylated gold nanoparticles under irradiation of megavoltage electrons

Purpose: Gold nanoparticles (GNP) have significant potential as radiosensitizer agents due to their distinctive properties. Several studies have shown that the surface modification of nanoparticles with methyl polyethylene glycol (mPEG) can increase their biocompatibility. However, the present study investigated the radiosensitization effects of mPEG-coated GNP (mPEG-GNP) in B16F10 murine melanoma cells under irradiation of 6 MeV Electron beam.Materials and methods: The synthesized GNP were characterized by UV-Visible spectroscopy, dynamic light scattering, transmission electron microscopy, and zeta potential. Enhancement of radiosensitization was evaluated by the clonogenic assay at different radiation doses of megavoltage electron beams.Results: It was observed that mPEG-GNP with a hydrodynamic size of approximately 50 nm are almost spherical and cellular uptake occurred at all concentrations. Both proliferation efficiency and survival fraction decreased with increasing mPEG-GNP concentration. Furthermore, significant GNP sensitization occurred with a maximum dose enhancement factor of 1.22 at a concentration of 30 μM.Conclusions: Pegylated-GNP are taken up by B16F10 cancer cells and cause radiosensitization in the presence of 6 MeV electrons. The radiosensitization effects of GNP may probably be due to biological processes. Therefore, the underlying biological mechanisms beyond the physical dose enhancement need to be further clarified.

Monte Carlo and analytic simulations in nanoparticle-enhanced radiation therapy.

Analytical and Monte Carlo simulations have been used to predict dose enhancement factors in nanoparticle-enhanced X-ray radiation therapy. Both simulations predict an increase in dose enhancement in the presence of nanoparticles, but the two methods predict different levels of enhancement over the studied energy, nanoparticle materials, and concentration regime for several reasons. The Monte Carlo simulation calculates energy deposited by electrons and photons, while the analytical one only calculates energy deposited by source photons and photoelectrons; the Monte Carlo simulation accounts for electron–hole recombination, while the analytical one does not; and the Monte Carlo simulation randomly samples photon or electron path and accounts for particle interactions, while the analytical simulation assumes a linear trajectory. This study demonstrates that the Monte Carlo simulation will be a better choice to evaluate dose enhancement with nanoparticles in radiation therapy.

Spatial distributions of dose enhancement around a gold nanoparticle at several depths of proton Bragg peak

Gold nanoparticles (GNPs) have been recognized as a promising candidate for a radiation sensitizer. A proton beam incident on a GNP can produce secondary electrons, resulting in an enhancement of the dose around the GNP. However, little is known about the spatial distribution of dose enhancement around the GNP, especially in the direction along the incident proton. The purpose of this study is to determine the spatial distribution of dose enhancement by taking the incident direction into account. Two steps of calculation were conducted using the Geant4 Monte Carlo simulation toolkit. First, the energy spectra of 100 and 195MeV protons colliding with a GNP were calculated at the Bragg peak and three other depths around the peak in liquid water. Second, the GNP was bombarded by protons with the obtained energy spectra. Radial dose distributions were computed along the incident beam direction. The spatial distributions of the dose enhancement factor (DEF) and subtracted dose (Dsub) were then evaluated. The spatial DEF distributions showed hot spots in the distal radial region from the proton beam axis. The spatial Dsub distribution isotropically spread out around the GNP. Low energy protons caused higher and wider dose enhancement. The macroscopic dose enhancement in clinical applications was also evaluated. The results suggest that the consideration of the spatial distribution of GNPs in treatment planning will maximize the potential of GNPs.

금 나노입자를 활용한 두부 모의피폭체에서의 선량증가 효과 평가

두부 모의피폭체를 활용하여 MV X, <TEX>${\gamma}$</TEX>선에서의 선량증가 효과와 금 나노입자의 크기, 물질의 농도에 대한 의존성을 평가하였다. MCNPX code를 이용하여 Monte Carlo 시뮬레이션 기법을 적용하였으며, 입사 에너지는 4, 6, 10, 15 MV X선, Co60 <TEX>${\gamma}$</TEX>선을 사용하였다. 두부 모의피폭체 내에 종양을 묘사하고 내부에 25, 75, 125 nm 직경의 금 나노입자를 삽입하였다. 나노입자의 농도는 5, 15, 25 mg/g을 적용하였으며, 선량 증가 물질이 없을 때를 기준으로 하여 선량증가비를 산출하였다. 입사 에너지가 낮을수록, 선량증가 물질의 농도가 높을수록 높은 선량증가비를 나타내었다. 나노입자의 크기는 입사 에너지가 낮고, 물질의 농도가 높을수록 상대적으로 높은 의존성을 보였다. 금 나노입자를 이용한 선량증가 효과를 나타내는데 기초자료로 활용할 수 있을 것으로 사료된다. The effect of dose enhancement was evaluated using Snyder head phantom, dependence on size of gold nanoparticle and material concentration in megavoltage X, <TEX>${\gamma}$</TEX>-ray. Monte Carlo simulation using MCNPX was used for 4, 6, 10, 15 MV and Co-60 <TEX>${\gamma}$</TEX>-ray. Described the tumor in Snyder head phantom, gold nanoparticle of 25, 75, 125nm diameter was inserted inside tumor. Concentration of dose enhancement material was used for 5, 15, 25 mg/g and dose enhancement factor was calculated on the basis of the no dose enhancement material. The lower incident energy and the higher concentration of material were that high dose enhancement factor is indicated. The size of gold nanoparticle had relatively high dependence on lower incident energy and higher concentration of material. It will increase dose inside the tumor, and be additional effect of use of gold nanoparticles in radiation therapy.

Abstract 3716: Potent radiation enhancement with VX-984, a selective DNA-PKcs inhibitor for the treatment of NSCLC

Abstract Ionizing radiation (IR), which is widely used for the treatment of cancer, causes double-strand breaks (DSBs) in DNA. If left unrepaired, these DSBs are lethal to the cell. DNA-dependent protein kinase (DNA-PK) is a key enzyme in the non-homologous end joining (NHEJ) pathway that repairs DSBs caused by IR, or chemotherapeutic agents that cause DSBs such as doxorubicin. The goal of these studies was to characterize the radiation enhancing effects of VX-984, a selective and potent ATP-competitive inhibitor of the catalytic subunit of DNA-PK (DNA-PKcs), with a focus on non-small cell lung cancer (NSCLC) cells and tumor xenografts. VX-984 enhances the cytotoxicity of IR in a panel of cancer cell lines including NSCLC cell lines in vitro with dose enhancement factors (DEF) greater than 3. Notably, VX-984 combined with IR in normal human lung fibroblasts minimally enhanced the cytotoxicity compared to IR alone. Additionally, VX-984 decreased DNA-PKcs autophosphorylation on S2056 both in vitro and in vivo in NSCLC cells and attenuated the decay of the DNA damage markers γH2AX and pKAP1 in response to IR. In NSCLC PDX models VX-984, in combination with IR (2 Gy x 3), caused durable complete responses while IR alone only led to a delay in tumor growth, consistent with delayed DNA damage repair. In these models, the combination of VX-984 and IR was well tolerated. These data demonstrate that VX-984 is a potent radiation-enhancing agent and provide a strong rationale for the use of VX-984 in combination with IR for the treatment of NSCLC. Citation Format: Diane Boucher, Russell Hoover, Yuxin Wang, Yong Gu, David Newsome, Pamella Ford, Cameron Moody, Veronique Damagnez, Reiko Arimoto, Shawn Hillier, Mark Wood, William Markland, Brenda Eustace, Kevin Cottrell, Marina Penney, Brinley Furey, Kirk Tanner, John Maxwell, Paul Charifson. Potent radiation enhancement with VX-984, a selective DNA-PKcs inhibitor for the treatment of NSCLC. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3716.

Dose Distribution and Dose Enhancement by Using Gadolinium Nanoparticles Implant in Brain Tumor in Stereotactic Brachytherapy

BackgroundThe photoelectric and pair production processes increase when high-energy photons interact with materials with high atomic number Z. The energy loss results in a dose enhancement at the target implanted with these materials. This will lead to a higher active dose to be delivered to tumor, while sparing healthy tissues around the target volume. Objective and methodThe objective of this work was to compute the radial dose enhancement, using GEANT4 based Monte Carlo simulations, at and near a 1×1×1cm3 brain tumor implanted with different concentrations of gadolinium nanoparticles when using 192Ir, 137Cs and 60Co, brachytherapy sources with parallel beam geometry. ResultsOur outcomes show a dose enhancement factor of 1.45 for a concentration of 70mg of gadolinium in the tumor when irradiated with 0.38MeV γ-photon from 192Ir source. It was also observed that this dose enhancement increased with increasing gadolinium concentration in the target and with photon energy. ConclusionGadolinium nanoparticles are groundbreaking agents with strong advantageous potential in cancer radiotherapy due to the fact that they enhance the radiation dose within the tumor.

SU‐F‐T‐630: Energy Spectral Study On Lipiodol After Trans‐Arterial Chemoembolization Using the Flattened and Unflattened Photon Beams

Purpose:SBRT combining transarterial chemoembolization with Lipiodol is expected to improve local control. Our showed that the dose enhancement effect in the Lipiodol with 10X flattening filter free (FFF) was inserted. This study was to investigate the energy fluence variations of electron in the Lipiodol using flattened (FF) and FFF beams.Methods:FF and FFF for 6X and 10X beams by TrueBeam were used in this study. The Lipiodol (3 X 3 X 3 cm3) was located at the depth of 5 cm in water, the dose enhancement factor (DEF) and energy fluence were calculated by Monte Carlo (MC) calculations (PHITS).Results:DEFs with FF and FFF of 6X were 17.1% and 24.3% at rebuild‐up region in the Lipiodol (5.3cm depth), 7.0% and 17.0% at the center of Lipiodol (6.5cm depth), and −13.2% and −8.2% at behind Lipiodol (8.3cm depth). DEFs with FF and FFF of 10X were 21.7% and 15.3% at rebuild‐up region, 8.2% and 10.5% at the center of Lipiodol, and −14.0% and −8.6% at behind Lipiodol. Spectral results showed that the FFF beam contained more low‐energy (0–0.3MeV) component of electrons than FF beam, and FF beam contained more high‐energy (over 0.3MeV) electrons than FFF beam in Lipiodol. Behind the Lipiodol, build‐down effect with FF beam was larger than FFF beam because FF beam contained more high energy electrons. The difference of DEFs between FFF and FF beams for 6X were larger than for 10X. This is because 10X beam contained more high‐energy electrons. Conclusion: It was found that the 6XFFF beam gives the largest change of energy fluence and the largest DEF in this study. These phenomena are mainly caused by component of low‐energy electrons, and this energy is almost correspond to the boundary of photo electronic dominant and Compton scattering dominant region for photon beams.

SU‐F‐T‐659: Nanoparticle‐Aided Eye Plaque Radiotherapy

Purpose:Eye plaque brachytherapy is one of the approaches for radiotherapy treatment for ocular cancers: retinoblastoma and choroidal melanoma. This study, investigates the potential benefits of using gold nanoparticles to enhance therapeutic efficacy during eye plaque brachytherapy.Methods:The EYE PHYSICS Inc. Plaque Simulator program distributed by IsoAid, LLC, Port Richey, Florida was used. It is based on the superposition of dose contributions from individual seeds following the TG–43 formalism. Dose enhancement factor (DEF) values for feasible nanoparticle concentrations from previous studies was used to investigate the benefit of using nanoparticles to enhance dose to tumour or reduce dose to healthy tissue. The dose enhancement factor (DEF) represents the ratio of the dose deposited in tumour with nanoparticles divided by dose deposited in the tumour without nanoparticles. The investigation was done for I–125 and Pd–103 typical sources employed for eye plaque brachytherapy. The prescription dose used is 85 Gy.Results:Lower dose enhancement values were obtained for Pd–103. With DEF of 2 due to gold nanoparticles, critical structure doses reduce by a factor of 2. Optic disc dose is 6.69 Gy and 4.571 Gy, opposite retina dose is 4.064 and 2.484 Gy, lens dose is 12.66 Gy and 9.870 Gy, and fovea dose is 9.85 Gy and 7.275 Gy. With DEF of 3 due to gold nanoparticles, critical structure doses reduce by a factor of 3. Optic disc dose is 4.352 Gy and 2.975 Gy, opposite retina dose is 2.644 Gy and 1.618 Gy, lens dose is 8.322 Gy and 6.427 Gy, and fovea dose is 4.815 Gy and 4.737 Gy.Conclusion:The results of this research predict that using gold nanoparticles will lead to major sparing of dose to critical structures. The finding provides more impetus for the development of nanoparticle–aided brachytherapy.

TU‐H‐CAMPUS‐TeP3‐02: In‐Situ Dose Painting Using Gold Nanoparticles Released From Cylindrically Shaped Fiducials During External Beam Radiation Therapy

Purpose:Recent studies have shown that the presence of Gold Nanoparticles (GNPs) in tumor tissue can lead to significant dose enhancement (DE) during External Beam Radiation Therapy (EBRT). In this in‐silico study we investigate EBRT with in‐situ dose painting using GNPs released from cylindrically shaped GNP‐loaded fiducials.Methods:Reported Biologically Target/Tumor Volumes (BTVs) for 12 prostate carcinoma patients were employed in this study. Distribution of the GNPs after burst release from the fiducial (1.5mm diameter and 5mm length) located in the center of the spherically assumed BTV were modeled by isotropic and free diffusion without boundary condition and under the assumption of superposition. An experimentally determined diffusion coefficient for 10nm nanoparticles was adapted for investigating other GNP sizes (2, 5, 15, and 20nm) using the Stokes‐Einstein equation. The maximum size of GNPs to achieve a minimal DE Factor (DEF) of 1.1 for 6MV EBRT using a fiducial‐load of 30mg/g was calculated for typical periods of 14 and 21 days after implantation. Further, the minimal fiducial‐load needed to achieve a clinically significant DEF of 1.2 was computed for 2nm GNPs.Results:Results showed that a minimal DEF of 1.1 could be reached for the smallest patient BTV using a maximal GNP size of 10nm and 20nm after 14 and 21 days, respectively. With increasing BTV smaller GNPs are required to ensure the same DEF. In particular, the largest BTV requires 2nm GNPs for periods of 14 and 21 days. Meanwhile, the required fiducial‐load to reach a minimal DEF of 1.2 after 14 days was found in the range of 17mg/g and 59mg/g for all reported BTVs.Conclusion:This preliminary study indicates a strong dependence on GNP size and fiducial‐load to realize a significant DE. The findings avail further research towards development of GNP‐loaded fiducials for significantly enhancing radiotherapy for cancer patients.

SU‐G‐TeP3‐05: In Vitro Demonstration of Endothelial Dose Enhancement Due to Gold Nanoparticles During Low‐Voltage Radiotherapy

Purpose:Oraya Therapy uses low‐voltage, stereotactic, highly targeted X‐rays for the treatment of wet age‐related macular degeneration (AMD) — offering a new option for patients worldwide. Neovascular endothelial cells play a crucial role in the pathogenesis of this disease. This in‐vitro study investigates the potential of gold nanoparticles (GNP) to enhance endothelial cell damage during low‐voltage radiotherapy towards potential applications in the treatment of wet‐AMD.Methods:Primary human umbilical cord vein endothelium cells (HUVEC) were treated with 1.4 nm sized GNPs for 24 hrs and then irradiated with variable X‐ray doses using an Oraya therapy system (100 kVp) or a Small Animal Radiation and Research platform (SARRP) at other beam qualities (up to 220 kVp). Radio‐sensitization was assessed by clonogenic assays. Variable concentrations of GNPs (0.05 mg/ml, 0.1 mg/ml, 0.25 mg/ml, 0.5 mg/ml, and 1 mg/ml) where employed. The dose enhancement factor (DEF) was calculated as the ratio of radiation doses required to give the same biological effect (survival factor, SF) with and without GNPs.Results:Preliminary results show DEFs of up to 2.62 for the different combinations of x‐ray doses and GNP concentrations and beam qualities. In general the DEF increased with increase in GNP concentration. However, for high doses the effect of GNP becomes less apparent likely due to already high cell kill by the radiation alone.Conclusion:The findings suggest that targeted GNPs can play a significant synergistic role in enhancing stereotactic radiosurgery for wet AMD. The results also provide impetus for ongoing studies to find the optimal synergy between the doses or beam energies and GNPs concentration. This will benefit in‐vivo studies towards development of nanoparticle‐aided radiotherapy for treatment of wet‐AMD and potentially ocular cancers.

TU‐H‐CAMPUS‐TeP3‐05: Evaluation of the Microscopic Dose Enhancement in the Nanoparticle‐Enhanced Auger Therapy

Purpose:The aim of this study is to apply Monte Carlo simulations to investigate the nanoparticle dose enhancement for Auger therapy.Methods:Two nanoparticle fabrications were considered: nanoshell and nanosphere. In the first step, a single nanoparticle was irradiated with Auger emitters. The electrons were scored in a phase space at the outer surface of the nanoparticle with Geant4‐Penelope. In the second step, the previously recorded phase space was used as a source and placed at the center of a cell‐size water phantom. The nanoscale dose was evaluated in water around the nanoparticle with Geant4‐DNA. The dose enhancement factor (DEF) is defined as the ratio of doses with and without nanoparticles. The nanoparticles were replaced by corresponding water nanoparticle with the same size and volume source which represents typical situation of Auger emitters without nanoparticle. Various sizes/materials of nanoparticles and isotopes were considered.Results:Nanoshell ‐ Microscopic dose was increased up to 130% at 20 – 100 nm distances from the surface of Au‐125I nanoshell. However, dose at less than 20 nm distance was reduced due to absorbed low energy electrons in gold nanoshell. The amounts and regions of the dose enhancement were dependent on nanoshell size, materials, and isotopes. Nanosphere ‐ The increased amounts of electrons up to 300% and reduced average energy with nanosphere were observed compared with water nanoparticle. We observed localized dose enhancement (up to a factor 3.6) in the immediate vicinity (&lt; 50 nm) of Au‐125 I nanosphere. The dose enhancement patterns vary according to nanosphere sizes and isotopes.Conclusion:We conclude that Auger therapy with nanoparticles can lead to change of electron energy spectrum and dose enhancements at certain range. The dose enhancement patterns vary according to nanoparticle sizes, materials, and isotopes.This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIP: Ministry of Science, ICT and Future Planning) (No. NRF‐2013M2B2B1075776)

TU‐H‐CAMPUS‐TeP3‐03: Dose Enhancement by Gold Nanoparticles Around the Bragg Peak of Proton Beams

Purpose:To make clear the spatial distribution of dose enhancement around gold nanoparticles (GNPs) located near the proton Bragg peak, and to evaluate the potential of GNPs as a radio sensitizer.Methods:The dose enhancement by electrons emitted from GNPs under proton irradiation was estimated by Geant4 Monte Carlo simulation toolkit in two steps. In an initial macroscopic step, 100 and 195 MeV proton beams were incident on a water cube, 30 cm on a side. Energy distributions of protons were calculated at four depths, 50% and 75% proximal to the Bragg peak, 100% peak, and 75% distal to the peak (P50, P75, Peak, and D75, respectively). In a subsequent microscopic step, protons with the energy distribution calculated above were incident on a 20 nm diameter GNP in a nanometer‐size water box and the spatial distribution of dose around the GNP was determined for each energy distribution. The dose enhancement factor (DEF) was also deduced.Results:The dose enhancement effect was spread to several tens of nanometers in the both depth and radial directions. The enhancement area increased in the order of P50, P75, Peak, and D75 for both cases with 100 and 195 MeV protons. In every position around the Bragg peak, the 100 MeV beam resulted in a higher dose enhancement than the 195 MeV beam. At P75, the average and maximum DEF were 3.9 and 17.0 for 100 MeV, and 3.5 and 16.2 for 195 MeV, respectively. These results indicate that lower energy protons caused higher dose enhancement in this incident proton energy range.Conclusion:The dose enhancement around GNPs spread as the position in the Bragg peak region becomes deeper and depends on proton energy. It is expected that GNPs can be used as a radio sensitizer with consideration of the location and proton beam energy.

WE‐H‐BRA‐05: Investigation of LET Spectral Dependence of the Biological Effects of Therapeutic Protons

Purpose:To investigate the dependence of biologic effect (BE) of therapeutic protons on LET spectra by comparing BEs with equal dose‐averaged LET (LETd) derived from different LET spectra using high‐throughput in vitro clonogenic survival assays.Methods:We used Geant4 to design the relevant experimental setups and perform the dose, LETd, and LET spectra calculations for spot‐scanning protons. The clonogenic assay was performed using the H460 lung cancer cell line cultured in 96‐well plates. In the first experimental setup (S1), cells were irradiated using 127.4 MeV protons with a 93.22 mm Lucite buildup resulting in a LETd value of 3.4 keV/µm in the cell layer. In the second experimental setup (S2), cells were irradiated by a combination of 127.4 MeV and 136.4 MeV protons with a 96.61 mm Lucite buildup. The LETd values in the cell layer were 11.4 keV/µm and 1.5 keV/µm respectively, but an average LETd of 3.4 keV/µm was obtained by adjusting the relative fluence of each beam. Ten discrete dose levels with 0.5 Gy increments were delivered.Results:In the two setups, the energies or LET spectra were different but resulted in identical LETd values. We quantified the dose contributions from high‐LET (≥10 keV/µm, threshold determined by previous experiments) events in the LET spectra separately for these two setups as 3.2% and 10.5%. The biologic effects at each identical dose level yielded statistically significant different survival curves (extra sum‐of‐squares F‐test, P&lt;0.0001). The second setup with a higher contribution from high‐LET events exhibited the higher biologic effect with a dose enhancement factor of 1.17±0.03 at 0.10 surviving fraction.Conclusion:The dose‐averaged LET may not be an accurate indicator of the biological effects of protons. Detailed LET spectra may need to be considered explicitly to accurately quantify the biologic effects of protons.Funding Support: U19 CA021239‐35, R21 CA187484‐01 and MDACC‐IRG

MO‐AB‐BRA‐02: Modeling Nanoparticle‐Eluting Spacer Degradation During Brachytherapy Application with in Situ Dose‐Painting

Purpose:Brachytherapy application with in situ dose‐painting using gold nanoparticles (GNP) released from GNP‐loaded brachytherapy spacers has been proposed as an innovative approach to increase therapeutic efficacy during brachytherapy. This work investigates the dosimetric impact of slow versus burst release of GNP from next generation biodegradable spacers.Methods:Mathematical models were developed based on experimental data to study the release of GNP from a spacer designed with FDA approved poly(lactic‐co‐glycolic acid) (PLGA) polymer. The diffusion controlled released process and PLGA polymer degradation kinetics was incorporated in the calculations for the first time. An in vivo determined diffusion coefficient was used for determining the concentration profiles and corresponding dose enhancement based on initial GNP‐loading concentrations of 7 mg/g.Results:The results showed that there is significant delay before the concentration profile of GNP diffusion in the tumor is similar to that when burst release is assumed as in previous studies. For example, in the case of burst release after spacer administration, it took up to 25 days for all the GNP to be released from the spacer using diffusion controlled release process only. However, it took up to 45 days when a combined model for both diffusion and polymer degradation processes was used. Based on the tumor concentration profiles, a significant dose enhancement factor (DEF &gt;20%), could be attained at a tumor distances of 5 mm from a spacer loaded with 10 nm GNP sizes.Conclusion:The results highlight the need to take the slow release of GNP from spacers and factors such as biodegradation of polymers into account in research development of GNP‐eluting spacers for brachytherapy applications with in‐situ dose‐painting using gold nanoparticles. The findings suggest that I‐125 may be the more appropriate for such applications given the relatively longer half‐live compared to other radioisotopes like Pd‐103 and Cs‐131.

Dual Action Enhancement of Gold Nanoparticle Radiosensitization by Pentamidine in Triple Negative Breast Cancer.

Triple negative breast cancer (TNBC) is an aggressive disease with a high risk of recurrence and death. Here, we present a novel strategy to enhance the radiotherapy of TNBC by combining gold nanoparticles (AuNPs) with pentamidine, a clinically approved anti-parasitic agent with anti-cancer properties. The radiosensitization effects of PEG-stabilized AuNPs (PEG-AuNPs) in combination with pentamidine were evaluated in two human TNBC cell lines (MDA-MB-231 and MDA-MB-436). Our results showed that PEG-AuNPs alone sensitized both cell lines to radiation, achieving dose enhancement factors of 1.26 and 1.15 in MDA-MB-231 and MDA-MB-436, respectively. In combination with pentamidine, the greatest dose enhancement was achieved in MDA-MB-231 after 24 h of treatment with 500 μM PEG-AuNPs and 20 μM pentamidine (dose enhancement factor of 1.55). Based on the in vitro data, it is projected that this combination would result in a 10 log increase in cell kill compared to radiation alone in a clinical setting, where 50 Gy is administered to breast cancer patients in 25 fractions over 5 weeks. Studies to elucidate the underlying mechanism of radiosensitization revealed that the adsorption of pentamidine onto the PEG-AuNP surface increased the cellular uptake of gold compared to PEG-AuNPs alone. In addition, the combination resulted in a significantly greater number of residual DNA double-strand breaks compared to that of either agent alone after a 2 Gy dose. Taken together, the dual action of pentamidine on the physical and biological pathways of radiosensitization by PEG-AuNPs results in superior radiotherapeutic effects of the combined treatment group in MDA-MB-231.

Ocular brachytherapy dosimetry for 103Pd and 125I in the presence of gold nanoparticles: a Monte Carlo study.

The aim of the present Monte Carlo study is to evaluate the variation of energy deposition in healthy tissues in the human eye which is irradiated by brachytherapy sources in comparison with the resultant dose increase in the gold nanoparticle (GNP)‐loaded choroidal melanoma. The effects of these nanoparticles on normal tissues are compared between 103Pd and 125I as two ophthalmic brachytherapy sources. Dose distribution in the tumor and healthy tissues has been taken into account for both brachytherapy sources. Also, in certain points of the eye, the ratio of the absorbed dose by the normal tissue in the presence of GNPs to the absorbed dose by the same point in the absence of GNPs has been calculated. In addition, differences of the absorbed dose in the tumor observed in the comparison of simple water phantom and actual simulated human eye in presence of GNPs are also a matter of interest that have been considered in the present work. The difference between the eye globe and the water phantom is more obvious for 125I than that of the 103Pd when the ophthalmic dosimetry is done in the presence of GNPs. Whenever these nanoparticles are utilized in enhancing the absorbed dose by the tumor, the use of 125I brachytherapy source will greatly amplify the amount of dose enhancement factor (DEF) in the tumor site without inflicting much damage to healthy organs, when compared to the 103Pd source. For instance, in the concentration of 30 mg GNPs, the difference amongst the calculated DEF for 125I between these phantoms is 5.3%, while it is 2.45% for 103Pd. Furthermore, in Monte Carlo studies of eye brachytherapy, more precise definition of the eye phantom instead of a water phantom will become increasingly important when we use 125I as opposed to 103Pd.PACS number(s): 87.53.Jw, 87.85.Rs, 87.10.Rt

Evaluating the effect of Zinc Oxide nanoparticles doped with Gadolinium on dose enhancement factor by PRESAGE dosimeter

Evaluating the effect of Zinc Oxide nanoparticles doped with Gadolinium on dose enhancement factor by PRESAGE dosimeter

EP-1911: Evaluating the effect of Zinc Oxide nanoparticles doped with Gadolinium on dose enhancement factor

EP-1911: Evaluating the effect of Zinc Oxide nanoparticles doped with Gadolinium on dose enhancement factor