Rachel Sidebottom, Jason Allison, Ethan Aulwes, Brittany Broder, Matthew Freeman, Per Magnelind, Fesseha Mariam, Frank Merrill, Levi Neukirch, Tamsen Schurman, James Sinnis, Zhaowen Tang, Dale Tupa, Joshua Tybo, Carl Wilde, Michelle Espy
Purpose: Proton radiography may guide proton therapy cancer treatments with beam’s-eye-view anatomical images and a proton-based estimation of proton stopping power. However, without contrast enhancement, proton radiography will not be able to distinguish tumor from tissue. To provide this contrast, functionalized, high-Z nanoparticles that specifically target a tumor could be injected into a patient before imaging. We conducted this study to understand the ability of gold, as a high-Z, biologically compatible tracer, to differentiate tumors from surrounding tissue.
Approach: Acrylic and gold phantoms simulate a tumor tagged with gold nanoparticles (AuNPs). Calculations correlate a given thickness of gold to levels of tumor AuNP uptake reported in the literature. An identity, ×3, and ×7 proton magnifying lens acquired lens-refocused proton radiographs at the 800-MeV LANSCE proton beam. The effects of gold in the phantoms, in terms of percent density change, were observed as changes in measured transmission. Variable areal densities of acrylic modeled the thickness of the human body.
Results: A 1-μm-thick gold strip was discernible within 1 cm of acrylic, an areal density change of 0.2%. Behind 20 cm of acrylic, a 40-μm gold strip was visible. A 1-cm-diameter tumor tagged with 1 × 105 50-nm AuNPs per cell has an amount of contrast agent embedded within it that is equivalent to a 65-μm thickness of gold, an areal density change of 0.63% in a tissue thickness of 20 cm, which is expected to be visible in a typical proton radiograph.
Conclusions: We indicate that AuNP-enhanced proton radiography might be a feasible technology to provide image-guidance to proton therapy, potentially reducing off-target effects and sparing nearby tissue. These data can be used to develop treatment plans and clinical applications can be derived from the simulations.
Proton radiography is a promising imaging technique that can be used to improve the treatment plan quality for proton therapy, by providing accurate estimates of proton stopping power. While a proton radiograph has accurate information about proton stopping power, it also has an inherently low tissue contrast for diagnostic purposes, as compared to X-ray imaging. The nature of energetic, massive protons as a radiographic probe is that they require a high-Z tracer to provide sufficient proton scatter in order to delineate target structures. Gold nanoparticles could be that ideal tracer due to a Z = 79, and their biocompatibility. Here the detection thresholds for gold-nanoparticle targeted tumors are evaluated using instantaneous, 800-MeV proton radiography, at the Los Alamos Neutron Science Center. Data is compared against MRI data in pre-clinical mouse models with 4T1 tumors directly injected with gold nanoparticle solution. The proton radiography system is then optimized using novel collimation schemes, including a dark field proton radiographic setup, that aimed to increase sensitivity and reduce dose. Results evaluated here are extrapolated to 211-MeV proton radiographic energy, to compare against expectations at clinical treatment energies. At that lower energy, proton radiography is more sensitive to the multiple Coulomb scattering introduced by a high-Z tracer.
Proton radiography is a potentially valuable tool for the image guidance of proton therapy cancer treatment. While proton therapy is desirable due to its high dose deposition accuracy, proton radiography, which could, in theory, be applied simultaneously to treatment, has an intrinsically low soft tissue contrast, making it difficult to visualize tumors. To enhance this tumor contrast, high-Z nanoparticles could be targeted to a tumor before imaging. To assess the efficacy of gold as a contrast agent, phantoms consisting of gold leaf mounted on acrylic backing were developed to simulate a tumor tagged with gold nanoparticles (AuNPs). Calculations are presented to correlate a given thickness of gold with scenarios for tagging cancers with AuNPs, in terms of the size of the functionalized nanoparticles, the diameter of the tumor, as well as the efficiency by which the nanoparticles are taken up by the malignant cells. These calculations determined phantoms that best describe particular tagging conditions, and are also applicable to ex vivo specimens made by injecting AuNPs into a mouse model. Using a ×3 proton magnifying lens with the 800-MeV LANSCE proton beam, a 1-μm-thick Au foil was radiographically discernible within 1 cm of acrylic, representing sensitivity to a material percent density change of 0.2%. This indicates that AuNP-enhanced proton radiography could be used to characterize small tumors, allowing for early detection and treatment of malignant tissues, as well as for in situ imaging for enhanced treatment localization.
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