Brian Duh-Lan Lee

Preclinical assessment of a zwitterionic tantalum oxide nanoparticle X-ray contrast agent.

Tantalum oxide nanoparticles show great potential as the next generation of X-ray contrast media. Recently, we reported advances in tantalum oxide nanoparticles and identified improvements that were required for such particles to progress further. Namely, the viscosity of concentrated particles, the amount of retention in reticuloendothelial (RES) tissues, and the effect of large quantities of particles on the kidneys after administration were all identified as critical factors which needed further study, understanding, and development. Here, we report on a zwitterionic siloxane polymer nanoparticle coating that reduced the viscosity of concentrated solutions of particles by a factor of 5, decreased tissue retention of injected particles by a factor of 10, and, importantly, did not induce pathological responses in the kidneys.

Biological performance of a size-fractionated core-shell tantalum oxide nanoparticle x-ray contrast agent.

ObjectivesMetal-containing nanoparticles show great promise as x-ray contrast media and could enable reduced radiation dose, increased contrast, and the visualization of smaller anatomic features. In this study, we report progress toward these goals using a size-fractionated core-shell tantalum oxide nanoparticle contrast agent. Materials and MethodsA core-shell tantalum oxide nanoparticle contrast agent was synthesized and size fractionated for preclinical investigation of biodistribution, blood half-life, organ retention, and histopathology. Fractionated agent was injected at anticipated clinical dose and at 3 times the anticipated clinical dose to evaluate biological performance. Computed tomography (CT) imaging studies were also performed to evaluate short-term clearance kinetics and new imaging applications. ResultsImproved control of 2-diethylphosphatoethylsilane-TaO nanoparticle size resulted in significantly reduced retention of injected tantalum. In vivo and in vitro CT imaging studies demonstrated short-term biodistribution differences in the kidney between small-molecule iodinated contrast media and fractionated 2-diethylphosphatoethylsilane-TaO, as well as preliminary data about new “Ta-only” imaging applications using multienergy CT image acquisition. ConclusionsSize-fractionated core-shell tantalum oxide nanoparticles with a well-defined particle size distribution have several key features required of clinically viable vascular imaging compounds and may be used in developing multienergy CT imaging applications.

Functional Imaging of Oxidative Stress with a Novel PET Imaging Agent, 18F-5-Fluoro-l-Aminosuberic Acid

Glutathione is the predominant endogenous cellular antioxidant, playing a critical role in the cellular defensive response to oxidative stress by neutralizing free radicals and reactive oxygen species. With cysteine as the rate-limiting substrate in glutathione biosynthesis, the cystine/glutamate transporter (system xc-) represents a potentially attractive PET biomarker to enable in vivo quantification of xc- activity in response to oxidative stress associated with disease. We have developed a system xc- substrate that incorporates characteristics of both natural substrates, l-cystine and l-glutamate (l-Glu). l-aminosuberic acid (l-ASu) has been identified as a more efficient system xc- substrate than l-Glu, leading to an assessment of a series of anionic amino acids as prospective PET tracers. Herein, we report the synthesis and in vitro and in vivo validation of a lead candidate, 18F-5-fluoro-aminosuberic acid (18F-FASu), as a PET tracer for functional imaging of a cellular response to oxidative stress with remarkable tumor uptake and retention. Methods: 18F-FASu was identified as a potential PET tracer based on an in vitro screening of compounds similar to l-cystine and l-Glu. Affinity toward system xc- was determined via in vitro uptake and inhibition studies using oxidative stress–induced EL4 and SKOV-3 cells. In vivo biodistribution and PET imaging studies were performed in mice bearing xenograft tumors (EL4 and SKOV-3). Results: In vitro assay results determined that l-ASu inhibited system xc- as well as or better than l-Glu. The direct comparison of uptake of tritiated compounds demonstrated more efficient system xc- uptake of l-ASu than l-Glu. Radiosynthesis of 18F-FASu allowed the validation of uptake for the fluorine-bearing derivative in vitro. Evaluation in vivo demonstrated primarily renal clearance and uptake of approximately 8 percentage injected dose per gram in SKOV-3 tumors, with tumor-to-blood and tumor-to-muscle ratios of approximately 12 and approximately 28, respectively. 18F-FASu uptake was approximately 5 times greater than 18F-FDG uptake in SKOV-3 tumors. Dynamic PET imaging demonstrated uptake in EL4 tumor xenografts of approximately 6 percentage injected dose per gram and good tumor retention for at least 2 h after injection. Conclusion: 18F-FASu is a potentially useful metabolic tracer for PET imaging of a functional cellular response to oxidative stress. 18F-FASu may provide more sensitive detection than 18F-FDG in certain tumors.

Evaluation of the novel USPIO GEH121333 for MR imaging of cancer immune responses.

Tumor-associated macrophages (TAM) maintain a chronic inflammation in cancers, which is associated with tumor aggressiveness and poor prognosis. The purpose of this study was to: (1) evaluate the pharmacokinetics and tolerability of the novel ultrasmall superparamagnetic iron oxide nanoparticle (USPIO) compound GEH121333; (2) assess whether GEH121333 can serve as a MR imaging biomarker for TAM; and (3) compare tumor MR enhancement profiles between GEH121333 and ferumoxytol. Blood half-lives of GEH121333 and ferumoxytol were measured by relaxometry (n = 4 each). Tolerance was assessed in healthy rats injected with high dose GEH121333, vehicle or saline (n = 4 each). Animals were monitored for 7 days regarding body weight, complete blood counts and serum chemistry, followed by histological evaluation of visceral organs. MR imaging was performed on mice harboring MMTV-PyMT-derived breast adenocarcinomas using a 7 T scanner before and up to 72 h post-injection (p.i.) of GEH121333 (n = 10) or ferumoxytol (n = 9). Tumor R1, R2* relaxation rates were compared between different experimental groups and time points, using a linear mixed effects model with a random effect for each animal. MR data were correlated with histopathology. GEH121333 showed a longer circulation half-life than ferumoxytol. Intravenous GEH121333 did not produce significant adverse effects in rats. All tumors demonstrated significant enhancement on T1, T2 and T2*-weighted images at 1, 24, 48 and 72 h p.i. GEH121333 generated stronger tumor T2* enhancement than ferumoxytol. Histological analysis verified intracellular compartmentalization of GEH121333 by TAM at 24, 48 and 72 h p.i. MR imaging with GEH121333 nanoparticles represents a novel biomarker for TAM assessment. This new USPIO MR contrast agent provides a longer blood half-life and better TAM enhancement compared with the iron supplement ferumoxytol. Copyright