Contrast-enhanced proton radiographic sensitivity limits for tumor detection

Abstract

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, $\times 3$ , and $\times 7$ 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 $1\text{-}\mu m$ -thick gold strip was discernible within 1 cm of acrylic, an areal density change of 0.2%. Behind 20 cm of acrylic, a $40\text{-}\mu m$ gold strip was visible. A 1-cm-diameter tumor tagged with $1\times {10}^5$ 50-nm AuNPs per cell has an amount of contrast agent embedded within it that is equivalent to a $65\text{-}\mu m$ 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.

Keywords: cancer; gold nanoparticles; proton radiography; proton therapy; tumor assessment.

Fig. 1

(a) Schematic of a cuboidal cell tagged with functionalized AuNPs and (b) a depiction of a volume of tumor comprised of many cells, where all of the gold is compressed into a layer at the bottom. The thickness of this gold layer ($T_{\mathrm{Au}}$) corresponds to the thickness of gold leaf or foil used for the phantoms constructed in this article.

Fig. 2

Phantom fabrication process. (a) Two square acrylic blanks, $\sim 5\mathrm{cm}\times 5\mathrm{cm}$ in cross section and 0.5 cm thick, side-by-side. (b) Acrylic blanks attached with nylon screws in each of the four corners. (c) Crosshatch design of gold-leaf strips, showing the number of layers of gold leaf in each column/row. (d) Assembled gold-leaf phantom encased by acrylic blanks, with $15\mathrm{mm}\times 15\mathrm{mm}$ pattern of gold leaf in the center.

Fig. 3

Proton–material interactions. Coulomb scattering increases with target areal density and $Z$. Tagging a tumor with high $Z$ nanoparticles increases the tumor’s areal density, increasing the amount of Coulomb scattering interactions, making the object visible by proton radiography.

Fig. 4

Proton magnetic lenses with particle transport diagrams. Each lens comprised of four quadrupole magnets refocuses the scattered proton distribution at the image plane. (a) The identity lens has a 12-cm FoV and $200\text{-}\mu \mathrm{m}$ spatial resolution. (b) A $\times 3$ magnifier provides an $80\text{-}\mu \mathrm{m}$ spatial resolution and a 40-mm FoV. (c) A $\times 7$ magnifier has a 1.5-cm FoV and $25\text{-}\mu \mathrm{m}$ spatial resolution.

Fig. 5

Experimental set-up of gold phantoms on variable thicknesses of acrylic to simulate different amounts of healthy tissue. Proton beam moves from left to right. Gold phantoms range in thicknesses from 20 to $200\mu \mathrm{m}$.

Fig. 6

(a) Calibrated x-ray radiograph and (b) proton radiograph ($\times 3$ magnification) of a gold-leaf phantom. All Au-leaf strips are visible in x-ray. 128-, 32-, and 8-layer Au-leaf strips, corresponding to gold thicknesses of 18, 4.5, 1.2, and $0.28\mu \mathrm{m}$, respectively, are visible in the calibrated radiograph.

Fig. 7

Calibrated proton radiographs (magnification with identity lens) of gold-foil phantoms through 0.15, 10, and 20 cm of acrylic.

Fig. 8

CNR as a function of the percent density change of tissue added by gold leaf. The sensitivity threshold was determined by eye to be a CNR of 2, because all steps above that threshold were visible.

Fig. 9

CNR as a function of the percent density change of tissue (acrylic) added by gold leaf. CNR and percent density change were calculated for gold leaf phantoms on variable thicknesses of acrylic (a) 1.5-mm acrylic, (b) 100-mm acrylic, and (c) 200-mm acrylic. Blue dots represent observed CNR values, and red dots represent CNR values corrected by known proton flux. The red dashed line represents the linear nature of the fixed CNR values versus percent density change.

Fig. 10

The level of nanoparticle tagging per cell of size $L_{\text{cell}}=10\mu \mathrm{m}$ to discern tumors in 25 cm tissue with proton radiography. For different scenarios, Eq. (10) gives the required average number of nanoparticles tagging each cell to produce density contrast of 0.4%, adequate to discern tumors. Studies observing as many as ${10}^5$ AuNP per cell have been reported.