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

Abstract

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 highmore » 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.« less

Authors:
;  [1]; ;  [1];  [2];  [1];  [2]; ;  [3]; ;  [4]
  1. Brigham and Women’s Hospital, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA (United States)
  2. (United States)
  3. Oraya Therapeutics Inc., Newark, CA (United States)
  4. University of Massachusetts Boston, Boston, MA (United States)
Publication Date:
OSTI Identifier:
22649426
Resource Type:
Journal Article
Resource Relation:
Journal Name: Medical Physics; Journal Volume: 43; Journal Issue: 6; Other Information: (c) 2016 American Association of Physicists in Medicine; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; 61 RADIATION PROTECTION AND DOSIMETRY; BEAMS; BIOLOGICAL EFFECTS; CONCENTRATION RATIO; EYES; GOLD; IN VITRO; IN VIVO; NANOPARTICLES; NEOPLASMS; RADIATION DOSES; RADIOTHERAPY

Citation Formats

Yasmin-Karim, S, Makrigiorgos, GM, Moreau, M, Ngwa, W, University of Massachusetts Lowell, Lowell, MA, Kumar, R, Northeastern University, Boston, MA, Hanlon, J, Arnoldussen, M, Hempstead, J, and Celli, J. SU-G-TeP3-05: In Vitro Demonstration of Endothelial Dose Enhancement Due to Gold Nanoparticles During Low-Voltage Radiotherapy. United States: N. p., 2016. Web. doi:10.1118/1.4957085.
Yasmin-Karim, S, Makrigiorgos, GM, Moreau, M, Ngwa, W, University of Massachusetts Lowell, Lowell, MA, Kumar, R, Northeastern University, Boston, MA, Hanlon, J, Arnoldussen, M, Hempstead, J, & Celli, J. SU-G-TeP3-05: In Vitro Demonstration of Endothelial Dose Enhancement Due to Gold Nanoparticles During Low-Voltage Radiotherapy. United States. doi:10.1118/1.4957085.
Yasmin-Karim, S, Makrigiorgos, GM, Moreau, M, Ngwa, W, University of Massachusetts Lowell, Lowell, MA, Kumar, R, Northeastern University, Boston, MA, Hanlon, J, Arnoldussen, M, Hempstead, J, and Celli, J. 2016. "SU-G-TeP3-05: In Vitro Demonstration of Endothelial Dose Enhancement Due to Gold Nanoparticles During Low-Voltage Radiotherapy". United States. doi:10.1118/1.4957085.
@article{osti_22649426,
title = {SU-G-TeP3-05: In Vitro Demonstration of Endothelial Dose Enhancement Due to Gold Nanoparticles During Low-Voltage Radiotherapy},
author = {Yasmin-Karim, S and Makrigiorgos, GM and Moreau, M and Ngwa, W and University of Massachusetts Lowell, Lowell, MA and Kumar, R and Northeastern University, Boston, MA and Hanlon, J and Arnoldussen, M and Hempstead, J and Celli, J},
abstractNote = {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.},
doi = {10.1118/1.4957085},
journal = {Medical Physics},
number = 6,
volume = 43,
place = {United States},
year = 2016,
month = 6
}
  • Purpose: Tumor endothelial cell damage during radiation therapy may contribute significantly to tumor eradication and treatment efficacy. Gold nanoparticles (AuNPs) delivered preferentially to the walls of tumor blood vessels produce low-energy, short-range photoelectrons during external beam radiotherapy, boosting dose to the tumor microvasculature. In this study dosimetry at the single-cell level is used to estimate the anticipated AuNP-mediated dose enhancement to tumor endothelial cells during 6-MV X-ray irradiation. Methods and Materials: Endothelial cells are modeled as thin slabs with 100-nm-diameter AuNPs attached within the blood vessel. The number of photoelectrons emitted per AuNP per gray of X-rays is computed atmore » multiple points along the external beam central axis by use of a Monte Carlo-generated energy fluence spectrum. The energy deposited from AuNP emissions to the endothelium is calculated based on an analytic method incorporating the energy-loss formula of Cole. The endothelial dose enhancement factor (EDEF) is the ratio of the overall (externally plus internally generated) dose to endothelial cells in the presence of AuNPs to the dose without AuNPs (from the external beam only). Results: At 20-cm depth, the EDEF is 1.7 (70% dose increase) for an intravascular AuNP concentration of 30 mg/g. Most of this dose enhancement arises from the low-energy (approximately 100 keV) portion of the linear accelerator X-ray spectrum. Furthermore, for AuNP concentrations ranging from 7 to 140 mg/g, EDEF values of 1.2 to 4.4 (20-340% dose increase) are calculated. Conclusions: In contrast to calculations assuming that AuNPs distributed homogeneously throughout the target volume (macrodosimetry), our cellular microdosimetry calculations predict a major dose enhancement to tumor microvasculature from conventional linear accelerator X-rays. This effect may enable the delivery of ablative therapeutic doses to these sensitive microstructures while maintaining established dose constraints for the organs at risk.« less
  • 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 themore » 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.« less
  • Purpose: To probe physical evidences of the dose enhancement due to a low/clinically-relevant concentration of gold nanoparticles (GNPs) and Yb-169 gamma rays using PRESAGE dosimeters. Methods: A PRESAGE cuvette was placed at approximately 2 mm above the plane containing three novel Yb-169 brachytherapy seeds (3.2, 3.2, and 5.3 mCi each). Two types of PRESAGE dosimeters were used – plain PRESAGEs (controls) and PRESAGEs loaded with 0.02 wt. % of GNPs (GNP-PRESAGEs). Each PRESAGE dosimeter was irradiated with different time durations (0 to 24 hours) to deliver 0, 4, 8, 16 and 24 Gy of dose. For a reference/comparison, both typesmore » of PRESAGEs were also irradiated using 250 kVp x-rays with/without Er-filter to deliver 0, 3, 10, and 30 Gy of dose. Er-filter was used to emulate Yb-169 spectrum using 250 kVp x-rays. The absorption spectra of PRESAGEs were measured using a UV spectrophotometer and used to determine the corresponding optical densities (ODs). Results: GNP-PRESAGEs exposed to Yb-169 sources showed ∼65% increase in ODs compared with controls. When exposed to Er-filtered and unfiltered 250 kVp x-rays, they produced smaller increases in ODs, ∼41% and ∼37%, respectively. There was a linear relationship between ODs and delivered doses with a goodness-of-fit (R2) greater than 0.99. Conclusion: A notable increase in the ODs (∼65%) was observed for GNP-PRESAGEs irradiated by Yb-169 gamma rays. Considering the observed OD increases, it was highly likely that Yb-169 gamma rays were more effective than both Er-filtered and unfiltered 250 kVp x-rays, in terms of producing the dose enhancement. Due to several unknown factors (e.g., possible difference in the dose response of GNP-PRESAGEs vs. PRESAGEs), however, a further investigations is necessary to establish the feasibility of quantifying the exact amount of macroscopic or microscopic/local GNP-mediated dose enhancement using PRESAGE or similar volumetric dosimeters. Supported by DOD/PCRP grant W81XWH-12-1-0198 This investigation was supported by DOD/PCRP grant W81XWH-12-1-0198.« less
  • 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 themore » 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.« less
  • Purpose: The aim of this study is to quantify and to compare the dose enhancement factor from gold nanoparticles (AuNP) to tumor endothelial cells for different concentrations of AuNP, and clinical MV beam configurations. Methods: Tumor endothelial cells are modeled as slabs measuring 10 Multiplication-Sign 10 Multiplication-Sign 2 {mu}m. A spherical AuNP is simulated on the surface of the endothelial cell, within the blood vessel. 6 MV photon beams with and without the flattening filter are investigated for different field sizes, depths in material and beam modulation. The incident photon energy spectra for each configuration is generated using EGSnrc. Themore » dose enhancement in the tumor endothelial cell is found using an analytical calculation. The endothelial dose enhancement factor is defined to be the ratio of the dose deposited with and without AuNPs. Results: It is found that clinical beam parameters may be chosen to maximize the effect of gold nanoparticles during radiotherapy. This effect is further amplified {approx}20% by the removal of the flattening filter. Modulation of the clinical beam with the multileaf collimator tends to decrease the proportion of low energy photons, therefore providing less enhancement than the corresponding open field. Conclusions: The results of this work predict a dose enhancement to tumor blood vessel endothelial cells using conventional therapeutic (MV) x-rays and quantify the relative change in enhancement with treatment depth and field size.« less