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TH-C-T-6C-04: Estimation of Tumor Dose Enhancement Due to Gold Nanoparticles During Typical Radiation Treatments: A Preliminary Monte Carlo Study

Purpose: To computationally demonstrate possible tumordose enhancement due to the use of goldnanoparticles and to provide quantitative estimates of this tumordose enhancement during typical radiation treatments.Method and Materials: This investigation was conducted with several phantom test cases that simulated typical radiation treatments using orthovoltage x‐rays, high energy photon beams from linear accelerators, and gamma rays from a brachytherapy source. Specifically, possible dose enhancement within a tumor loaded with goldnanoparticles was calculated by Monte Carlo calculations when the phantoms were irradiated by 140 kVp x‐rays, 4 and 6 MV photon beams, and 192 Ir gamma rays. Based on published mice studies, the current study considered three levels of gold concentration within the tumor: 7, 18, and 30 mg Au / g tumor. The Monte Carlo calculations were performed with the BEAMnrc/DOSXYZnrc code system for the external beam cases and with the MCNP5 code for the 192 Ir cases, respectively. Results: The dose enhancement over the entire tumor volume considered for the 140 kVp x‐ray case can be at least a factor of 2 at an achievable gold concentration of 7 mg Au /g tumor. The tumordose enhancement for the cases involving the 4 and 6 MV photon beams ranged from about 18% to 60%, depending on the amount of gold within the tumor and photon beam qualities. For the 192 Ir cases, the dose enhancement within the tumor region ranged from 5% to 31%, depending on radial distance and gold concentration level. Conclusion: The tumordose can be enhanced significantly by using goldnanoparticles during typical radiation treatments, assuming that the findings from previous mice studies would be applicable in humans. Conflict of Interest: This investigation was supported in part by PHS Grant No. CA 10953 awarded by the National Cancer Institute, Department of Health and Human Services.

SU‐FF‐T‐324: Modifications of Megavoltage Photon Beams for Gold Nanoparticle‐Aided Radiation Therapy (GNRT): A Monte Carlo Study

Purpose: To produce megavoltage photon beams capable of achieving clinically significant (> 10%) macroscopic tumordose enhancement during goldnanoparticle‐aidedradiation therapy (GNRT). Method and Materials: GNRT is an emerging treatment modality currently under development, based on the following observations: a) high tumor specificity of goldnanoparticles due to passive extravasation; b) significant tumordose enhancement during x‐ray irradiation as a result of increased photoelectric absorption due to high atomic number (Z) of gold. A previous Monte Carlo study found that no meaningful tumordose enhancement would occur during GNRT with typical megavoltage photon beams, even after the removal of the flattening filter from linear accelerators. Therefore, the current Monte Carlo study investigated a number of ways to further increase the amount of low energy photons in the beam and consequently to achieve clinically significant tumordose enhancement with photon beams in megavoltage range. Specifically, the macroscopic tumordose enhancement under the identical geometry was calculated using the BEAMnrc/DOSXYZnrc code as the following conditions changed: the energy of electron pencil beam incident on the target, the target thickness, and the target material.Results: The current results showed that the macroscopic dose enhancement up to 40 and 18% across the tumor volume could be achievable with unflattened 2 and 4 MV photon beams, respectively, at a reasonable gold concentration of 3% within the tumor, after the proposed changes in target thickness and material. These beams were found capable of producing clinically acceptable treatment plans for GNRT, in spite of their softer photon energy spectra and larger buildup doses, compared to conventional megavoltage beams at the same nominal photon energies. Conclusion: Clinically significant tumordose enhancement could be achievable during GNRT with megavoltage photon beams, provided that the proposed modifications to linear accelerators are made.

TU-H-CAMPUS-TeP3-04: Probing the Dose Enhancement Due to a Clinically-Relevant Concentration of Gold Nanoparticles and Yb-169 Gamma Rays Using PRESAGE Dosimeters

PURPOSEnTo 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.nnnMETHODSnA 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 types 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).nnnRESULTSnGNP-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.nnnCONCLUSIONnA 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.

WE-G-303-01: Physical Bases for Gold Nanoparticle Applications in Radiation Oncology and X-Ray Imaging

Over the last decade, there has been a growing interest in applying nanotechnology to cancer detection, treatment, and treatment monitoring. Advances in nanotechnology have enabled the fabrication of nanoparticles from various materials with different shapes and sizes. Nanoparticles can be accumulated preferentially within tumors by either “passive targeting” through a phenomenon typically known as “enhanced permeability and retention” or “active targeting” in which nanoparticles are conjugated with antibodies or peptides directed against tumor and/or stromal markers. The tumor specificity of nanoparticles in conjunction with their unique physicochemical properties offers many novel strategies for cancerntreatment and detection. For example, notable approaches in the radiationnoncology setting include the use of goldnnanoparticles for radiation response modulation of tumor or normal tissue and thermal ablation or hyperthermia treatment of tumors. Some of these approaches are currently being tested either on humans or on animals and, very likely, will become the clinical reality in the near future. Various computational and experimental techniques have also been applied to address unique research issues associated with nanoparticles and may become the standard tools for future investigations and clinical translations. Therefore, both clinicians and researchers may need to be properly educated about the basic principles as well as the promise of nanoparticle-based applications with regard to the future of cancer diagnostics and therapeutics.nThis symposium will familiarize the audience with the potential applications of nanoparticles in oncologicnimaging and therapy using specific illustrative examples. The audience will be properly oriented by these illustrative examples to the multiple avenues for collaborative research amongst interdisciplinary teams of physicists, clinicians, engineers, chemists, and biologists in industry and academia.nLearning Objectives:n1.xa0nUnderstand the physical bases of goldnnanoparticle applications for radiosensitization and x-ray fluorescence imagingn2.xa0nUnderstand the parameters that define goldnnanoparticle-mediated radiosensitization in biological systemsn3.xa0nUnderstand the potential of magnetic nanoparticle characterization of the microenvironmentn4.xa0nUnderstand the various strategies for radiolabeling of nanoparticles and their applicationsnS.C. and S.K. acknowledge support from MD Anderson Cancer Center, NIH (R01CA155446 and P30CA16672) and DoD (W81XWH-12-1-0198); J.W. acknowledges support from NIH (U54CA151662-01); W.C. acknowledges support from the University of Wisconsin-Madison, NIH (R01CA169365, P30CA014520, and T32CA009206), DoD (W81XWH-11-1-0644 and W81XWH-11-1-0648), and ACS (125246-RSG-13-099-01-CCE).

SU‐FF‐T‐45: A Procedure for Correcting the Effect of Detector Properties On Measured Profiles of Small Field MV X‐Ray Beams

Purpose: Very small fields and segments of area less than one square centimeter are routinely being used for IMRT and stereotactic radiosurgery. Accurate measurement of beam profile is essential for treatment planning.Ion chambers with very small cavity radius, specialized diodes and films are commonly used for these beam data measurement. The purpose of this investigation is both to study the effect of the detector properties on the measured beam profiles of the small field MV x‐ray beams and to apply the necessary correction to determine the real profiles. Method and Materials: Two ionization chambers with cavity radius of 2 mm and 1 mm, a stereotactic diode and XV film were used to measure the beam profiles of circular fields of stereotactic cones and small square fields defined by collimator jaws and MLC. The penumbra widths of the profiles were compared to study the effect of the physical properties of the detectors, such as, size, energy dependence and dose rate dependence on the measured beam profiles. The profiles measured by the larger ionization chamber were corrected for the detector size effect by using a semi‐empirical procedure [1] and was used as the reference profile to derive the detector response function of other detectors with smaller size and better spatial resolution. The detector response functions were then used to correct the measured profiles of small fields. Results: The differences in the profiles measured by different detectors were significantly reduced after the profiles were corrected with detector response functions. Conclusion: The accuracy of the profile measurement of small therapy beams can be significantly improved when appropriate corrections are applied to take into account the variation of detector response in different regions of the beam.

TH-AB-209-01: Making Benchtop X-Ray Fluorescence Computed Tomography (XFCT) Practical for in Vivo Imaging by Integration of a Dedicated High-Performance X-Ray Source in Conjunction with Micro-CT Functionality

PURPOSEnTo make benchtop x-ray fluorescence computed tomography (XFCT) practical for routine preclinical imaging tasks with gold nanoparticles (GNPs) by deploying, integrating, and characterizing a dedicated high-performance x-ray source and addition of simultaneous micro-CT functionality.nnnMETHODSnConsiderable research effort is currently under way to develop a polychromatic benchtop cone-beam XFCT system capable of imaging GNPs by stimulation and detection of gold K-shell x-ray fluorescence (XRF) photons. Recently, an ad hoc high-power x-ray source was incorporated and used to image the biodistribution of GNPs within a mouse, postmortem. In the current work, a dedicated x-ray source system featuring a liquid-cooled tungsten-target x-ray tube (max 160 kVp, ∼3 kW power) was deployed. The source was operated at 125 kVp, 24 mA. The tubes compact dimensions allowed greater flexibility for optimizing both the irradiation and detection geometries. Incident x-rays were shaped by a conical collimator and filtered by 2 mm of tin. A compact OEM cadmium-telluride x-ray detector was implemented for detecting XRF/scatter spectra. Additionally, a flat panel detector was installed to allow simultaneous transmission CT imaging. The performance of the system was characterized by determining the detection limit (10-second acquisition time) for inserts filled with water/GNPs at various concentrations (0 and 0.010-1.0 wt%) and embedded in a small-animal-sized phantom. The phantom was loaded with 0.5, 0.3, and 0.1 wt% inserts and imaged using XFCT and simultaneous micro-CT.nnnRESULTSnAn unprecedented detection limit of 0.030 wt% was experimentally demonstrated, with a 33% reduction in acquisition time. The reconstructed XFCT image accurately localized the imaging inserts. Micro-CT imaging did not provide enough contrast to distinguish imaging inserts from the phantom under the current conditions.nnnCONCLUSIONnThe system is immediately capable of in vivo preclinical XFCT imaging with GNPs. Micro-CT imaging will require optimization of irradiation parameters to improve contrast. Supported by NIH/NCI grant R01CA155446; This investigation was supported by NIH/NCI grant R01CA155446.

SU‐F‐T‐54: Determination of the AAPM TG‐43 Brachytherapy Dosimetry Parameters for A New Titanium‐Encapsulated Yb‐169 Source by Monte Carlo Calculations

PURPOSEnTo determine the AAPM TG-43 brachytherapy dosimetry parameters of a new titanium-encapsulated Yb-169 source designed to maximize the dose enhancement during gold nanoparticle-aided radiation therapy (GNRT).nnnMETHODSnAn existing Monte Carlo (MC) model of the titanium-encapsulated Yb-169 source, which was described in the current investigators published MC optimization study, was modified based on the source manufacturers detailed specifications, resulting in an accurate model of the titanium-encapsulated Yb-169 source that was actually manufactured. MC calculations were then performed using the MCNP5 code system and the modified source model, in order to obtain a complete set of the AAPM TG-43 parameters for the new Yb-169 source.nnnRESULTSnThe MC-calculated dose rate constant for the new titanium-encapsulated Yb-169 source was 1.05 ± 0.03 cGy per hr U, indicating about 10% decrease from the values reported for the conventional stainless steel-encapsulated Yb-169 sources. The source anisotropy and radial dose function for the new source were found similar to those reported for the conventional Yb-169 sources.nnnCONCLUSIONnIn this study, the AAPM TG-43 brachytherapy dosimetry parameters of a new titanium-encapsulated Yb-169 source were determined by MC calculations. The current results suggested that the use of titanium, instead of stainless steel, to encapsulate the Yb-169 core would not lead to any major change in the dosimetric characteristics of the Yb-169 source, while it would allow more low energy photons being transmitted through the source filter thereby leading to an increased dose enhancement during GNRT. Supported by DOD/PCRP grant W81XWH-12-1-0198 This investigation was supported by DOD/PCRP grant W81XWH-12-1- 0198.

SU-G-IeP3-07: High-Resolution, High-Sensitivity Imaging and Quantification of Intratumoral Distributions of Gold Nanoparticles Using a Benchtop L-Shell XRF Imaging System

PURPOSEnTo demonstrate the ability to perform high-resolution imaging and quantification of sparse distributions of gold nanoparticles (GNPs) within ex vivo tumor samples using a highly-sensitive benchtop L-shell x-ray fluorescence (XRF) imaging system.nnnMETHODSnAn optimized L-shell XRF imaging system was assembled using a tungsten-target x-ray source (operated at 62 kVp and 45 mA). The x-rays were filtered (copper: 0.08 mm & aluminum: 0.04 mm) and collimated (lead: 5 cm thickness, 3 cm aperture diameter) into a cone-beam in order to irradiate small samples or objects. A collimated (stainless steel: 4 cm thickness, 2 mm aperture diameter) silicon drift detector, capable of 2D translation, was placed at 90° with respect to the beam to acquire XRF/scatter spectra from regions of interest. Spectral processing involved extracting XRF signal from background, followed by attenuation correction using a Compton scatter-based normalization algorithm. Calibration phantoms with water/GNPs (0 and 0.00001-10 mg/cm3 ) were used to determine the detection limit of the system at a 10-second acquisition time. The system was then used to map the distribution of GNPs within a 12×11×2 mm3 slice excised from the center of a GNP-loaded ex vivo murine tumor sample; a total of 110 voxels (2.65×10-3 cm3 ) were imaged with 1.3-mm spatial resolution.nnnRESULTSnThe detection limit of the current cone-beam benchtop L-shell XRF system was 0.003 mg/cm3 (3 ppm). Intratumoral GNP concentrations ranging from 0.003 mg/cm3 (3 ppm) to a maximum of 0.055 mg/cm3 (55 ppm) and average of 0.0093 mg/cm3 (9.3 ppm) were imaged successfully within the ex vivo tumor slice.nnnCONCLUSIONnThe developed cone-beam benchtop L-shell XRF imaging system can immediately be used for imaging of ex vivo tumor samples containing low concentrations of GNPs. With minor finetuning/optimization, the system can be directly adapted for performing routine preclinical in vivo imaging tasks. Supported by NIH/NCI grant R01CA155446 This investigation was supported by NIH/NCI grant R01CA155446.

WE-H-206-03: Promises and Challenges of Benchtop X-Ray Fluorescence CT (XFCT) for Quantitative in Vivo Imaging

Lihong V. Wang: Photoacoustic tomography (PAT), combining non-ionizing optical and ultrasonic waves via the photoacoustic effect, provides in vivo multiscale functional, metabolic, and molecular imaging. Broad applications include imaging of the breast, brain, skin, esophagus, colon, vascular system, and lymphatic system in humans or animals. Light offers rich contrast but does not penetrate biological tissue in straight paths as x-rays do. Consequently, high-resolution pure optical imaging (e.g., confocal microscopy, two-photon microscopy, and optical coherence tomography) is limited to penetration within the optical diffusion limit (∼1 mm in the skin). Ultrasonic imaging, on the contrary, provides fine spatial resolution but suffers from both poor contrast in early-stage tumors and strong speckle artifacts. In PAT, pulsed laser light penetrates tissue and generates a small but rapid temperature rise, which induces emission of ultrasonic waves due to thermoelastic expansion. The ultrasonic waves, orders of magnitude less scattering than optical waves, are then detected to form high-resolution images of optical absorption at depths up to 7 cm, conquering the optical diffusion limit. PAT is the only modality capable of imaging across the length scales of organelles, cells, tissues, and organs (up to whole-body small animals) with consistent contrast. This rapidly growing technology promises to enable multiscale biological research and accelerate translation from microscopic laboratory discoveries to macroscopic clinical practice. PAT may also hold the key to label-free early detection of cancer by in vivo quantification of hypermetabolism, the quintessential hallmark of malignancy.nnnLEARNING OBJECTIVESn1. To understand the contrast mechanism of PAT 2. To understand the multiscale applications of PAT Benjamin M. W. Tsui: Multi-modality molecular imaging instrumentation and techniques have been major developments in small animal imaging that has contributed significantly to biomedical research during the past decade. The initial development was an extension of clinical PET/CT and SPECT/CT from human to small animals and combine the unique functional information obtained from PET and SPECT with anatomical information provided by the CT in registered multi-modality images. The requirements to image a mouse whose size is an order of magnitude smaller than that of a human have spurred advances in new radiation detector technologies, novel imaging system designs and special image reconstruction and processing techniques. Examples are new detector materials and designs with high intrinsic resolution, multi-pinhole (MPH) collimator design for much improved resolution and detection efficiency compared to the conventional collimator designs in SPECT, 3D high-resolution and artifact-free MPH and sparse-view image reconstruction techniques, and iterative image reconstruction methods with system response modeling for resolution recovery and image noise reduction for much improved image quality. The spatial resolution of PET and SPECT has improved from ∼6-12 mm to ∼1 mm a few years ago to sub-millimeter today. A recent commercial small animal SPECT system has achieved a resolution of ∼0.25 mm which surpasses that of a state-of-art PET system whose resolution is limited by the positron range. More recently, multimodality SA PET/MRI and SPECT/MRI systems have been developed in research laboratories. Also, multi-modality SA imaging systems that include other imaging modalities such as optical and ultrasound are being actively pursued. In this presentation, we will provide a review of the development, recent advances and future outlook of multi-modality molecular imaging of small animals.nnnLEARNING OBJECTIVESn1. To learn about the two major multi-modality molecular imaging techniques of small animals. 2. To learn about the spatial resolution achievable by the molecular imaging systems for small animal today. 3. To learn about the new multi-modality imaging instrumentation and techniques that are being developed. Sang Hyun Cho; X-ray fluorescence (XRF) imaging, such as x-ray fluorescence computed tomography (XFCT), offers unique capabilities for accurate identification and quantification of metals within the imaging objects. As a result, it has emerged as a promising quantitative imaging modality in recent years, especially in conjunction with metal-based imaging probes. This talk will familiarize the audience with the basic principles of XRF/XFCT imaging. It will also cover the latest development of benchtop XFCT technology. Additionally, the use of metallic nanoparticles such as gold nanoparticles, in conjunction with benchtop XFCT, will be discussed within the context of preclinical multimodal multiplexed molecular imaging.nnnLEARNING OBJECTIVESn1. To learn the basic principles of XRF/XFCT imaging 2. To learn the latest advances in benchtop XFCT development for preclinical imaging Funding support received from NIH and DOD; Funding support received from GE Healthcare; Funding support received from Siemens AX; Patent royalties received from GE Healthcare; L. Wang, Funding Support: NIH; COI: Microphotoacoustics; S. Cho, Yes:;NIH/NCI grant R01CA155446 DOD/PCRP grant W81XWH-12-1-0198.

TH-AB-204-12: Practical/ultrasensitive Benchtop Gold L-Shell XRF Imaging System with a Kilowatt-Range X-Ray Source and Silicon Drift Detector.

Purpose: nTo improve the sensitivity and throughput of a benchtop x-ray fluorescence (XRF) imaging system capable of locating and quantifying distributions of gold nanoparticles (GNPs) by detecting gold L-shell XRF photons from subcentimeter-sized ex vivo samples or superficial tumors for preclinical small animal studies. n nMethods: nA proof-of-principle L-shell XRF imaging system has been developed previously. Originally, the system was configured with a low-power (∼50 W) x-ray source (62 kVp, 0.8 mA) and a silicon PIN diode detector. The detection limit of the system was approximately 0.02 mg/cm3 (20 ppm) for an acquisition time of 10 min. Currently, the system has been retrofitted with a high-power (∼3 kW) x-ray source. The detector was replaced with a silicon drift detector (SDD) to handle the increased photon flux at the new settings (62 kVp, 45 mA). Calibration was performed using phantoms containing water/GNPs at a wide range of concentrations (0 and 0.0001–10 mg/cm3). The acquisition time was set to 10 s (60 times shorter than that used with the former configuration, to maintain the same overall x-ray fluence and dose). The XRF/scatter spectrum at 90° was acquired from each phantom. The data were processed to extract XRF signal from background, which was then corrected for attenuation using a Compton-scatter-based normalization algorithm. The corrected XRF signals were plotted vs. GNP concentration and analyzed to determine the detection limit. n nResults: nThe detection limit with the current configuration was found to be 0.007 mg/cm3 (7 ppm), a three-fold improvement compared to the former configuration for the same dose. n nConclusion: nBy adopting a high-power x-ray source and SDD, the material detection limit has been improved to a level comparable to that of a synchrotron-based system. Concurrently, much shorter acquisition time afforded by the higher photon flux makes the current setup practical for routine preclinical imaging tasks.