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Tantalum oxide nanoparticles as versatile contrast agents for X-ray computed tomography.

ABSTRACT: Here, we describe the synthesis, characterization and in vitro and in vivo performance of a series of tantalum oxide (TaO_x) based nanoparticles (NPs) for computed tomography (CT). Five distinct versions of 9-12 nm diameter silane coated TaO_x nanocrystals (NCs) were fabricated by a sol-gel method with varying degrees of hydrophilicity and with or without fluorescence, with the highest reported Ta content to date (78%). Highly hydrophilic NCs were left bare and were evaluated in vivo in mice for micro-CT of full body vasculature, where following intravenous injection, TaO_x NCs demonstrate high vascular CT contrast, circulation in blood for ∼3 h, and eventual accumulation in RES organs; and following injection locally in the mammary gland, where the full ductal tree structure can be clearly delineated. Partially hydrophilic NCs were encapsulated within mesoporous silica nanoparticles (MSNPs; TaO_x@MSNPs) and hydrophobic NCs were encapsulated within poly(lactic-co-glycolic acid) (PLGA; TaO_x@PLGA) NPs, serving as potential CT-imagable drug delivery vehicles. Bolus intramuscular injections of TaO_x@PLGA NPs and TaO_x@MSNPs to mimic the accumulation of NPs at a tumor site produce high signal enhancement in mice. In vitro studies on bare NCs and formulated NPs demonstrate high cytocompatibility and low dissolution of TaO_x. This work solidifies that TaO_x-based NPs are versatile contrast agents for CT.

SUBMITTER: Chakravarty S

PROVIDER: S-EPMC7185737 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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Tantalum oxide nanoparticles as versatile contrast agents for X-ray computed tomography.

Chakravarty Shatadru S Hix Jeremy M L JML Wiewiora Kaitlyn A KA Volk Maximilian C MC Kenyon Elizabeth E Shuboni-Mulligan Dorela D DD Blanco-Fernandez Barbara B Kiupel Matti M Thomas Jennifer J Sempere Lorenzo F LF Shapiro Erik M EM

Nanoscale 20200325 14

Here, we describe the synthesis, characterization and in vitro and in vivo performance of a series of tantalum oxide (TaO<sub>x</sub>) based nanoparticles (NPs) for computed tomography (CT). Five distinct versions of 9-12 nm diameter silane coated TaO<sub>x</sub> nanocrystals (NCs) were fabricated by a sol-gel method with varying degrees of hydrophilicity and with or without fluorescence, with the highest reported Ta content to date (78%). Highly hydrophilic NCs were left bare and were evaluated ...[more]

PMID: 32211669

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Project description:ObjectivesThe aim of this study was to produce and evaluate a proposed computed tomography (CT) contrast agent based on carboxybetaine zwitterionic (CZ)-coated soluble tantalum oxide (TaO) nanoparticles (NPs). We chose tantalum to provide superior imaging performance compared with current iodine-based clinical CT contrast agents. We developed the CZ coating to provide biological and physical performance similar to that of current iodinated contrast agents. In addition, the aim of this study was to evaluate the imaging, biological, and physicochemical performance of this proposed contrast agent compared with clinically used iodinated agents.Materials and methodsWe evaluated CT imaging performance of our CZ-TaO NPs compared with that of an iodinated agent in live rats, imaged centrally located within a tissue-equivalent plastic phantom that simulated a large patient. To evaluate vascular contrast enhancement, we scanned the rats' great vessels at high temporal resolution during and after contrast agent injection. We performed several in vivo CZ-TaO NP studies in healthy rats to evaluate tolerability. These studies included injecting the agent at the anticipated clinical dose (ACD) and at 3 times and 6 times the ACD, followed by longitudinal hematology to assess impact to blood cells and organ function (from 4 hours to 1 week). Kidney histological analysis was performed 48 hours after injection at 3 times the ACD. We measured the elimination half-life of CZ-TaO NPs from blood, and we monitored acute kidney injury biomarkers with a kidney injury assay using urine collected from 4 hours to 1 week. We measured tantalum retention in individual organs and in the whole carcass 48 hours after injection at ACD. Carboxybetaine zwitterionic TaO NPs were synthesized and analyzed in detail. We used multidimensional nuclear magnetic resonance to determine surface functionality of the NPs. We measured NP size and solution properties (osmolality and viscosity) of the agent over a range of tantalum concentrations, including the high concentrations required for standard clinical CT imaging.ResultsComputed tomography imaging studies demonstrated image contrast improvement of approximately 40% to 50% using CZ-TaO NPs compared with an iodinated agent injected at the same mass concentration. Blood and organ analyses showed no adverse effects after injection in healthy naive rats at 3 times the ACD. Retention of tantalum at 48 hours after injection was less than 2% of the injected dose in the whole carcass, which very closely matched the reported retention of existing commercial iodine-based contrast agents. Urine analysis of sensitive markers for acute kidney injury showed no responses at 1 week after injection at 3 times the ACD; however, a moderate response in the neutrophil gelatinase-associated lipocalin biomarker was measured at 24 and 48 hours. Compared with other TaO NPs reported in the literature, CZ-TaO NPs had relatively low osmolality and viscosity at concentrations greater than 200 mg Ta/mL and were similar in these physical properties to dimeric iodine-based contrast agents.ConclusionsWe found that a CZ-TaO NP-based contrast agent is potentially viable for general-purpose clinical CT imaging. Our results suggest that such an agent can be formulated with clinically viable physicochemical properties, can be biologically safe and cleared rapidly in urine, and can provide substantially improved image contrast at CT compared with current iodinated agents.

Project description:There are limited options for primary prevention of breast cancer (BC). Experimental procedures to locally prevent BC have shown therapeutic efficacy in animal models. To determine the suitability of FDA-approved iodine-containing and various metal-containing (bismuth, gold, iodine, or tantalum) preclinical nanoparticle-based contrast agents for image-guided intraductal (ID) ablative treatment of BC in rodent models, we performed a prospective longitudinal study to determine the imaging performance, local retention and systemic clearance, safety profile, and compatibility with ablative solution of each contrast agent. At least six abdominal mammary glands (>3 female FVB/JN mice and/or Sprague-Dawley rats, 10-11 weeks of age) were intraductally injected with commercially available contrast agents (Omnipaque® 300, Fenestra® VC, MVivoTM Au, MVivoTM BIS) or in-house synthesized tantalum oxide (TaOx) nanoparticles. Contrast agents were administered at stock concentration or diluted in 70% ethanol (EtOH) and up to 1% ethyl cellulose (EC) as gelling agent to assess their compatibility with our image-guided ablative procedure. Mammary glands were serially imaged by microCT for up to 60 days after ID delivery. Imaging data were analyzed by radiologists and deep learning to measure in vivo signal disappearance of contrast agents. Mammary glands and major organs were ultimately collected for histopathological examination. TaOx-containing solutions provided best imaging performance for nitid visualization of ductal tree immediately after infusion, low outward diffusion (<1 day) and high homogeneity. Of all nanoparticles, TaOx had the highest local clearance rate (46% signal decay as stock and 36% as ablative solution 3 days after ID injection) and exhibited low toxicity. TaOx-containing ablative solution with 1% EC caused same percentage of epithelial cell death (88.62% ± 7.70% vs. 76.38% ± 9.99%, p value = 0.089) with similar minimal collateral damage (21.56 ± 5.28% vs. 21.50% ± 7.14%, p value = 0.98) in mouse and rat mammary glands, respectively. In conclusion, TaOx-nanoparticles are a suitable and versatile contrast agent for intraductal imaging and image-guided ablative procedures in rodent models of BC with translational potential to humans.

Project description:Nanostructures have potential for use in biomedical applications such as sensing, imaging, therapeutics, and drug delivery. Among nanomaterials, gold nanostructures are of considerable interest for biomedical research, owing to their bio-inertness, controllable surface chemistry, X-ray opacity, and optical properties. Gold nanocages are particularly attractive for imaging and therapeutic applications, because they strongly absorb light in the near infra-red region which has high light transmission in tissue. However, the X-ray attenuation of nanocages is relatively low due to their hollow structure. In this study, for the first time, we sought to combine the attractive optical properties of nanoshells with the high payloads of solid nanoparticles and investigated their biomedical applications. Here, we report the engineering of Wulff in a cage nanoparticles via converting gold Wulff-shaped seeds into gold-silver core-shell structures and then performing a galvanic replacement reaction. The structure of these nanoparticles was determined using transition electron microscopy. This morphological transformation of gold nanoparticles shaped as truncated octahedrons into a complex Wulff in a cage nanoparticles during the reaction resulted in extensive changes in their optical properties that made these unique structures a potential contrast agent for photoacoustic imaging. We found that the Wulff in a cage nanoparticles had no adverse effects on the viabilities of J774A.1, Renca, and HepG2 cells at any of the concentrations tested. In vitro and in vivo experiments showed robust signals in both photoacoustic imaging and computed tomography. To the best of our knowledge, this is the first report of Wulff in a cage nanoparticles serving as a platform for multiple imaging modalities. This unique multifunctional nanostructure, which integrates the competencies of both core and shell structures, allows their use as contrast agents for photoacoustic imaging, computed tomography and as a potential agent for photothermal therapy.

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Tantalum oxide nanoparticles as versatile contrast agents for X-ray computed tomography.

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Tantalum oxide nanoparticles as versatile contrast agents for X-ray computed tomography.

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