Abstract
Computed tomography (CT) is one of the most commonly used clinical imaging modalities. There have recently been many reports of novel contrast agents for CT imaging. In particular, the development of gold nanoparticles (AuNP) as CT contrast agents is a topic of intense interest. AuNP have favorable characteristics for this application such as high payloads of contrast generating material, strong X-ray attenuation, excellent biocompatibility, tailorable surface chemistry, and tunable sizes and shapes. However, there have been conflicting reports on the role of AuNP size on their contrast generation for CT. We therefore sought to extensively investigate the AuNP size-CT contrast relationship. In order to do this, we synthesized AuNP with sizes ranging from 4 to 152 nm and capped them with 5 kDa m-PEG. The contrast generation of AuNP of different sizes was investigated with three clinical CT, a spectral photon counting CT (SPCCT) and two micro CT systems. X-ray attenuation was quantified as attenuation rate in Hounsfield units per unit concentration (HU/mM). No statistically significant difference in CT contrast generation was found among different AuNP sizes via phantom imaging with any of the systems tested. Furthermore, in vivo imaging was performed in mice to provide insight into the effect of AuNP size on animal biodistribution at CT dose levels, which has not previously been explored. Both in vivo imaging and ex vivo analysis with inductively coupled plasma optical emission spectroscopy (ICP-OES) indicated that AuNP that are 15 nm or smaller have long blood circulation times, while larger AuNP accumulated in the liver and spleen more rapidly. Therefore, while we observed no AuNP size effect on CT contrast generation, there is a significant effect of size on AuNP diagnostic utility.
Highlights
Computed tomography (CT) is a widely used clinical imaging technique that employs an X-ray source and a detector array to form images[1]
Spherical AuNPs whose core diameter varied from 4 to 152 nm were synthesized to assess their CT contrast properties. mPEG coating was used to modify the AuNP surfaces after the synthesis of AuNP. mPEG is widely used as a capping ligand to coat nanoparticles as it provides high stability, reduces reticuloendothelial system (RES) uptake and increases circulation times versus uncoated nanoparticles[52,53]
Described for many AuNP with coatings of long chain PEG molecules[58,59], we found a sustained blood circulation for 4 nm and 15 nm AuNP 2 hours after intravenous injection. 50 nm AuNP persist in the vasculature up to 1 hour after injection, start clearing from the blood stream. 79 nm and 100 nm AuNP are in the bloodstream at 5 minutes post-injection, but are rapidly cleared from the blood thereafter. 152 nm AuNP were cleared from the blood and taken up in other organs before the 5 minutes post-injection CT scan
Summary
Computed tomography (CT) is a widely used clinical imaging technique that employs an X-ray source and a detector array to form images[1]. Nanoparticles can carry higher payloads of contrast generating materials[15], and their shape, size and surface chemistry are usually tunable for specific biomedical applications[16]. They can have blood circulation times of several hours, while the blood circulation time of iodinated small molecules is measured in minutes[17,18]. To thoroughly understand the effect of AuNP size on CT contrast generation and pharmacokinetics/biodistribution, we report the characteristics of six AuNP formulations that range in size from 4 to 152 nm. We performed in vivo CT imaging with these AuNP to observe the pharmacokinetics and biodistribution of PEG-modified AuNP after intravenous administration in mice
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