Nanoparticle contrast agents for X-ray imaging applications

Abstract

X-ray imaging is the most widely used diagnostic imaging method in modern medicine and several advanced forms of this technology have recently emerged. Iodinated molecules and barium sulfate suspensions are clinically approved X-ray contrast agents and are widely used. However, these existing contrast agents provide limited information, are suboptimal for new X-ray imaging techniques and are developing safety concerns. Thus, over the past 15 years, there has been a rapid growth in the development of nanoparticles as X-ray contrast agents. Nanoparticles have several desirable features such as high contrast payloads, the potential for long circulation times, and tunable physicochemical properties. Nanoparticles have also been used in a range of biomedical applications such as disease treatment, targeted imaging, and cell tracking. In this review, we discuss the principles behind X-ray contrast generation and introduce new types of X-ray imaging modalities, as well as potential elements and chemical compositions that are suitable for novel contrast agent development. We focus on the progress in nanoparticle X-ray contrast agents developed to be renally clearable, long circulating, theranostic, targeted, or for cell tracking. We feature agents that are used in conjunction with the newly developed multi-energy computed tomography and mammographic imaging technologies. Finally, we offer perspectives on current limitations and emerging research topics as well as expectations for the future development of the field. This article is categorized under: Diagnostic Tools > in vivo Nanodiagnostics and Imaging Nanotechnology Approaches to Biology > Nanoscale Systems in Biology.

Keywords: CT; X-ray imaging; cell tracking; dual-energy mammography; long circulating; nanoparticles; renal clearance; targeted agents; theranostics.

FIGURE 1

Schematic depictions of (a) the photoelectric effect and (b) Compton scattering

FIGURE 2

(a) Spectral CT images of gold, iodine, the photoelectric effect, and Compton scattering of an artery phantom. (b) Conventional CT image compared to SPCCT images of gold, iodine, and water of the chest of a rabbit injected with AuNP followed by iodine. (c) Mass attenuation coefficients of various heavy metal elements and X-ray photon energy spectra at tube voltages of 80 and 120 kV (Reprinted with permission from Cormode et al. (2010, 2017) and Kim et al. (2019)). CT, computed tomography; SPCCT, spectral photon-counting CT

FIGURE 3

(a) Diagram of the urinary system with a detailed view of the kidney including components of nephron and glomerulus. (b) Schematic depiction of the three distinctive layers of the glomerular filtration barrier (Reprinted with permission from J. Liu, Yu, Zhou, and Zheng (2013) and Wang and Liu (2018))

FIGURE 4

(a) CT images of a mouse injected with 3.1 nm silver sulfide nanoparticles. (b) Segmentation data to visualize vascular contrast and kidney filtration of the same mouse immediately postinjection. (c) CT images of mice injected with small- and large-sized silver sulfide nanoparticles at 2 hr postinjection (Reprinted with permission from Hsu et al. (2019)). CT, computed tomography

FIGURE 5

CT images of a mouse injected with GSAN showing contrast enhancement in the (a) blood pool and (b) breast tumors. (b) DEM images of a mouse injected with GSAN showing vascular contrast. (d) Quantification of DEM contrast in the tumors compared to an iodinated agent (Reprinted with permission from Naha et al. (2016)). CT, computed tomography; DEM, dual-energy mammography; GSAN, gold silver alloy nanoparticles

FIGURE 6

(a) SEM image of bismuth nanoraspberries. (b) DOX release profiles following exposure to different pH conditions with or without laser irradiation. (c) CT images of tumors acquired prior to and after injection of bismuth nanoraspberries. (d) Tumor weights of control and different treatment groups (Reprinted with permission from Li, Hu, et al. (2018)). CT, computed tomography; DOX, doxorubicin; SEM, scanning electron microscopy

FIGURE 7

(a) DECT iodine and gold maps for hindlimb sarcomas in the groups treated with 5 Gy RT in conjunction with no AuNP (control), PEGylated AuNP (non-targeted), or RGD-functionalized AuNP (targeted). (b) Accumulation of liposomal iodine in the tumors following AuNP-augmented RT at varying radiation doses. (c) Tumor volume doubling time for mice treated with 5 Gy RT, targeted AuNP, and/or liposomal doxorubicin (Reprinted with permission from Ashton et al. (2018)). AuNP, gold nanoparticles; DECT, dual-energy CT; RT, radiotherapy

FIGURE 8

(a) Scheme showing the process of labeling cells with nanoparticles, followed by in vivo injection and CT imaging. (b) Schematic depiction of AuNP coated with glucose for labeling cells. In vivo CT imaging of the accumulation of antibody-targeted and AuNP-labeled T cells at a melanoma tumor in mouse: (c) before T-cell injection, (d) 24 hr post IV injection, (e) 48 hr postinjection, and (f) 72 hr postinjection. Circles demarcate the tumor area and the T-cell accumulation. In vivo CT imaging of gold-labeled exosomes in (g) control mouse brain, (h) striatal stroke region in a mouse model of acute stroke, and (i) a spinal cord lesion at 24 hr post intranasal administration of exosomes (Reprinted with permission from Betzer et al. (2015, 2017), Guo et al. (2019), and Meir et al. (2015)). AuNP, gold nanoparticles; CT, computed tomography