The preferential accumulation of gold nanoparticles within tumors and the increased photoelectric absorption due to the high atomic number of gold cooperatively account for the possibility of significant tumor dose enhancement during gold nanoparticle-aided radiation therapy (GNRT). Among the many conceivable ways to implement GNRT clinically, a brachytherapy approach using low-energy gamma-/x-ray sources (i.e. Eavg 40%) could be achievable using 125I, 50 kVp and 169Yb sources and gold nanoparticles. When calculated at 1.0 cm from the center of the source within a tumor loaded with 18 mg Au g−1, macroscopic dose enhancement was 116, 92 and 108% for 125I, 50 kVp and 169Yb, respectively. For a tumor loaded with 7 mg Au g−1, it was 68, 57 and 44% at 1 cm from the center of the source for 125I, 50 kVp and 169Yb, respectively. The estimated MDEF values for 169Yb were remarkably larger than those for 192Ir, on average by up to about 70 and 30%, for 18 mg Au and 7 mg Au cases, respectively. The current MC study also shows a remarkable change in the photoelectron fluence and spectrum (e.g. more than two orders of magnitude) and a significant production (e.g. comparable to the number of photoelectrons) of the Auger electrons within the tumor region due to the presence of gold nanoparticles during low-energy gamma-/x-ray irradiation. The radiation sources considered in this study are currently available and tumor gold concentration levels considered in this investigation are deemed achievable. Therefore, the current results strongly suggest that GNRT can be successfully implemented via brachytherapy with low energy gamma-/x-ray sources, especially with a high dose rate 169Yb source.

https://iopscience.iop.org/article/10.1088/0031-9155/54/16/004/pdf

The dosimetric feasibility of gold nanoparticle-aided radiation therapy (GNRT) via brachytherapy using low-energy gamma-/x-ray sources

The past decade has seen a dramatic increase in interest in the use of gold nanoparticles (GNPs) as radiation sensitizers for radiation therapy. This interest was initially driven by their strong absorption of ionizing radiation and the resulting ability to increase dose deposited within target volumes even at relatively low concentrations. These early observations are supported by extensive experimental validation, showing GNPs' efficacy at sensitizing tumors in both in vitro and in vivo systems to a range of types of ionizing radiation, including kilovoltage and megavoltage X rays as well as charged particles. Despite this experimental validation, there has been limited translation of GNP-mediated radiation sensitization to a clinical setting. One of the key challenges in this area is the wide range of experimental systems that have been investigated, spanning a range of particle sizes, shapes, and preparations. As a result, mechanisms of uptake and radiation sensitization have remained difficult to clearly identify. This has proven a significant impediment to the identification of optimal GNP formulations which strike a balance among their radiation sensitizing properties, their specificity to the tumors, their biocompatibility, and their imageability in vivo. This white paper reviews the current state of knowledge in each of the areas concerning the use of GNPs as radiosensitizers, and outlines the steps which will be required to advance GNP-enhanced radiation therapy from their current pre-clinical setting to clinical trials and eventual routine usage.

/pdf/roadmap-to-clinical-use-of-gold-nanoparticles-for-radiation-5d9umrbwwh.pdf

Roadmap to Clinical Use of Gold Nanoparticles for Radiation Sensitization.

There has been growing interest in the use of nanomaterials for a range of biomedical applications over the last number of years. In particular, gold nanoparticles (GNPs) possess a number of unique properties that make them ideal candidates as radiosensitizers on the basis of their strong photoelectric absorption coefficient and ease of synthesis. However, despite promising preclinical evidence in vitro supported by a limited amount of in vivo experiments, along with advances in mechanistic understanding, GNPs have not yet translated into the clinic. This may be due to disparity between predicted levels of radiosensitization based on physical action, observed biological response and an incomplete mechanistic understanding, alongside current experimental limitations. This paper provides a review of the current state of the field, highlighting the potential underlying biological mechanisms in GNP radiosensitization and examining the barriers to clinical translation.

/pdf/biological-mechanisms-of-gold-nanoparticle-3rc3idnbu4.pdf

Biological mechanisms of gold nanoparticle radiosensitization.

X-ray luminescence computed tomography (XLCT) is proposed as a new molecular imaging modality based on the selective excitation and optical detection of X-ray-excitable phosphor nanoparticles. These nano-sized particles can be fabricated to emit near-infrared (NIR) light when excited with X-rays, and, because because both X-rays and NIR photons propagate long distances in tissue, they are particularly well suited for in vivo biomedical imaging. In XLCT, tomographic images are generated by irradiating the subject using a sequence of programmed X-ray beams, while sensitive photo-detectors measure the light diffusing out of the subject. By restricting the X-ray excitation to a single, narrow beam of radiation, the origin of the optical photons can be inferred regardless of where these photons were detected, and how many times they scattered in tissue. This study presents computer simulations exploring the feasibility of imaging small objects with XLCT, such as research animals. The accumulation of 50 nm phosphor nanoparticles in a 2-mm-diameter target can be detected and quantified with subpicomolar sensitivity using less than 1 cGy of radiation dose. Provided sufficient signal-to-noise ratio, the spatial resolution of the system can be made as high as needed by narrowing the beam aperture. In particular, 1 mm spatial resolution was achieved for a 1-mm-wide X-ray beam. By including an X-ray detector in the system, anatomical imaging is performed simultaneously with molecular imaging via standard X-ray computed tomography (CT). The molecular and anatomical images are spatially and temporally co-registered, and, if a single-pixel X-ray detector is used, they have matching spatial resolution.

http://web.stanford.edu/~pratx/PDF/XLCT.pdf

X-Ray Luminescence Computed Tomography via Selective Excitation: A Feasibility Study

Purpose: Recent advances in nanotechnology have resulted in the manufacture of a plethora of nanoparticles of different sizes, shapes, core physicochemical properties and surface modifications that...

/pdf/nanoparticle-mediated-thermal-therapy-evolving-strategies-20e3f78y4w.pdf

Nanoparticle-mediated thermal therapy: Evolving strategies for prostate cancer therapy

A conventional x-ray fluorescence computed tomography (XFCT) technique requires monochromatic synchrotron x-rays to simultaneously determine the spatial distribution and concentration of various elements such as metals in a sample. However, the synchrotron-based XFCT technique appears to be unsuitable for in vivo imaging under a typical laboratory setting. In this study we demonstrated, for the first time to our knowledge, the possibility of performing XFCT imaging of a small animal-sized object containing gold nanoparticles (GNPs) at relatively low concentrations using polychromatic diagnostic energy range x-rays. Specifically, we created a phantom made of polymethyl methacrylate plastic containing two cylindrical columns filled with saline solution at 1 and 2 wt% GNPs, respectively, mimicking tumors/organs within a small animal. XFCT scanning of the phantom was then performed using microfocus 110 kVp x-ray beam and cadmium telluride (CdTe) x-ray detector under a pencil beam geometry after proper filtering of the x-ray beam and collimation of the detector. The reconstructed images clearly identified the locations of the two GNP-filled columns with different contrast levels directly proportional to gold concentration levels. On the other hand, the current pencil-beam implementation of XFCT is not yet practical for routine in vivo imaging tasks with GNPs, especially in terms of scanning time. Nevertheless, with the use of multiple detectors and a limited number of projections, it may still be used to image some objects smaller than the current phantom size. The current investigation suggests several modification strategies of the current XFCT setup, such as the adoption of the quasi-monochromatic cone/fan x-ray beam and XFCT-specific spatial filters or pinhole detector collimators, in order to establish the ultimate feasibility of a bench-top XFCT system for GNP-based preclinical molecular imaging applications.

https://iopscience.iop.org/article/10.1088/0031-9155/55/3/007/pdf

X-ray fluorescence computed tomography (XFCT) imaging of gold nanoparticle-loaded objects using 110 kVp x-rays

A nontoxic heat-sensitive gel containing 1.5 % (w/v) agar and 25 % (w/v) bovine serum albumin (BSA) was fabricated in this study. Optical density measurements with 808 nm near-infrared (NIR) laser indicated that, in spite of its BSA content, the current agar + BSA gel remained similar to agar only gel in terms of its optical response to NIR laser. The thermal response of the current agar + BSA gel to high temperatures was quantified using magnetic resonance imaging (MRI). According to the MRI measurements of T2 relaxation rate as a function of heating temperature, the current agar + BSA gel showed a linear response to heating temperatures between 65 and 80 °C, while it remained thermally stable at temperatures up to 80 °C. Therefore, the current agar + BSA gel can be used as thermal dosimeters or volumetric heat-sensitive gel phantoms in typical thermal therapy regime.

Agar-based heat-sensitive gel with linear thermal response over 65–80 °C

Purpose: To demonstrate the dose enhancement due to goldnanoparticles and kilovoltage x‐rays by experimental measurements using radio‐sensitive gel dosimeters. Method and Materials: The dose enhancement due to goldnanoparticles and kilovoltage x‐rays has been well demonstrated through in‐vitro, in‐vivo, and computational work. However, it has not been clearly shown by any physical measurements over a volume loaded with goldnanoparticles. This study attempted to demonstrate the dose enhancement across the phantom made of radio‐sensitive gel, known as MAGIC gel, uniformly mixed with goldnanoparticles at a concentration of 1 % by weight. Specifically, formaldehyde‐containing MAGIC gel, reportedly more radio‐sensitive than the conventional MAGIC gel, was poured into 2 mL cylindrical plastic containers serving as the phantoms for x‐ray irradiation. Seven of them had MAGIC gel only, while the remaining two were filled with MAGIC gel and goldnanoparticles. Each gel phantom was irradiated using 110 kVp x‐rays entered into the phantom from six different directions separated by 60°. The total dose delivered to the phantom ranged from 0 to 30 Gy. One phantom in each group was unirradiated and taken as the control. All phantoms were read using a 7T small animal MR scanner. The inverse T2 relaxation time (i.e., R2 value) for each phantom was plotted against the delivered dose to obtain the calibration curve. Results: Preliminary results suggest addition of goldnanoparticles to MAGIC gel did not significantly change the R2 value, at least at the currently tested gold concentration level. They also show there was more than 100% dose enhancement across the volume of the phantom. Conclusion: The current investigation provides, probably for the first time, a solid physical evidence for the dose enhancement under the given conditions. It also provides a strong support for the previous estimation of dose enhancement by the Monte Carlo method.

SU-FF-J-150: Experimental Demonstration of Dose Enhancement Due to Gold Nanoparticles and Kilovoltage X-Rays Using Radio-Sensitive Polymer Gel Dosimeter

Purpose: To demonstrate and quantify goldnanorods (GNRs)‐induced plasmonicheating inside breast tumor phantom during near‐infrared (NIR) laser illumination.Method and Materials: GNRs were fabricated using published procedures. Two types of breast gel phantoms were fabricated. The first phantom was nearly water‐equivalent as it was fabricated using 1.5% agar gel (98.5% water). The second phantom, on the other hand, was fabricated using a more turbid intralipid‐based gel (2% agar, 2% intralipid, and 96% water). Both phantoms contained an identical GNR‐filled cavity with 4 mm inner diameter. The cavity was filled with approximately 0.1 weight percent GNRs and located at the center of a quadrant of hemispherical phantom at 2.5 cm depth measured from the base of the phantom. Both phantoms were illuminated with an 808 nm NIR laser at 1 W power under the identical geometry. Thermocouples were used to measure the temperature changes within the cavity and surrounding medium. Results: There was significant difference between the two gel phantoms in terms of achievable temperature rise within a GNR‐filled cavity. For a 60 second illumination, the cavity inside an agar‐based gel phantom was heated up to 15°C above the background temperature, while there was a temperature change of only about 1.5°C within the cavity inside an intralipid‐based gel phantom. Conclusion: The current results suggest tumors inside breast tissue with high water content may be easily heated up to a few degrees above the surrounding body temperature within a short time interval (e.g., on the order of 10 seconds) without much difficulty. According to the current results, however, it might be difficult to achieve such a temperature change for tumors inside breast tissue similar to intralipid‐based gel in terms of its optical property. This work has been supported by the US Department of Defense, Breast Cancer Research Program, Concept Award, W81XWH‐08‐1‐0686.

SU-GG-J-119: Induction of Plasmonic Heating Inside Breast Tumor Phantom Using Gold Nanorods and Near-Infrared Laser

Purpose: To determine the concentration of gold(Au)nanoparticles presented within the tumor during in vivo demonstration of tumordose enhancement by detectinggoldfluorescence x‐rays. Method and Materials:Goldnanoparticle solution of 1% by weight in saline was prepared using commercially available goldnanoparticles with 1.9 nm core diameter. A cylindrical sample container (2.5 cm in diameter and 5.0 cm in height) was irradiated with 110 kVp and 200 mA x‐rays from conventional radiotherapy simulator for 40 seconds with 1 cm × 1 cm x‐ray beam at 85 cm source‐to‐surface distance (SSD) and spectrum was obtained using either Si‐PIN or CdTe photodiodedetector using a container‐to‐detector geometry to minimize unwanted photons entering the detector.Results: The spectrum collected using the Si detector successfully captured the AuLα and Lβfluorescence lines at 9.7 and 11.4 keV, respectively, well above the background. AuK lines could not be measured with Si‐PIN photodiode due to Si‐PIN detection inefficiency above 60 keV. To capture the AuK lines, CdTe photodiodedetector was employed which has high detection efficiency for energy range of AuK lines. The spectrum collected using CdTe detector clearly showed the AuKα2, Kα1, and Kβ lines corresponding to energies of 67.0, 68.8, and 77.9 keV, respectively. Conclusion: The magnitude of obtained Kαfluorescence signal (i.e. greater than 50% above all background scattering) is very encouraging considering the tested gold concentration. With more sophisticated geometry to minimize scattered photons reaching the detector,Aufluorescence output from K lines can be used to measure even lower concentrations of goldnanoparticles.Fluorescence output as a function of Au concentration can be developed to accurately measure goldnanoparticle concentration.

SU‐GG‐J‐67: Detection of Gold Fluorescence X‐Rays for the In‐Vivo Quantification of Gold Concentration During Gold Nanoparticle‐Aided Radiation Therapy (GNRT)

A. Siddiqi

Papers

X-ray fluorescence computed tomography (XFCT) imaging of gold nanoparticle-loaded objects using 110 kVp x-rays

Agar-based heat-sensitive gel with linear thermal response over 65–80 °C

SU-FF-J-150: Experimental Demonstration of Dose Enhancement Due to Gold Nanoparticles and Kilovoltage X-Rays Using Radio-Sensitive Polymer Gel Dosimeter

SU-GG-J-119: Induction of Plasmonic Heating Inside Breast Tumor Phantom Using Gold Nanorods and Near-Infrared Laser

SU‐GG‐J‐67: Detection of Gold Fluorescence X‐Rays for the In‐Vivo Quantification of Gold Concentration During Gold Nanoparticle‐Aided Radiation Therapy (GNRT)