Radiopaque tantalum oxide (TaOx) nanoparticles can be fabricated with a variety of surface chemistries enabling the use of computed tomography to image a vast array of important biolgical phenomena and nanoparticle delivery schemes.
Diabetes is associated with hepatic metabolic dysfunction predisposing patients to drug-induced liver injury. Mouse models of type 2 diabetes (T2D) have dramatically reduced expression of organic anion transporting polypeptide (OATP)1A1, a transporter expressed in hepatocytes and in the kidneys. The effects of diabetes on OATP1B2 expression are less studied and less consistent. OATP1A1 and OATP1B2 both transport endogenous substrates such as bile acids and hormone conjugates as well as numerous drugs including gadoxetate disodium (Gd-EOB-DTPA). As master pharmacokinetic regulators, the altered expression of OATPs in diabetes could have a profound and clinically significant influence on drug therapies. Here, we report a method to noninvasively measure OATP activity in T2D mice by quantifying the transport of hepatobiliary-specific gadolinium-based contrast agents (GBCAs) within the liver and kidneys using dynamic contrast–enhanced MRI (DCE-MRI). By comparing GBCA uptake in control and OATP knockout mice, we confirmed liver clearance of the hepatobiliary-specific GBCAs, Gd-EOB-DTPA, and gadobenate dimeglumine, primarily though OATP transporters. Then, we measured a reduction in the hepatic uptake of these hepatobiliary GBCAs in T2D ob/ob mice, which mirrored significant reductions in the mRNA and protein expression of OATP1A1 and OATP1B2. As these GBCAs are U.S. Food and Drug Administration–approved agents and DCE-MRI is a standard clinical protocol, studies to determine OATP1B1/1B3 deficiencies in human individuals with diabetes can be easily envisioned.
Longitudinal radiological monitoring of biomedical devices is increasingly important, driven by the risk of device failure following implantation. Polymeric devices are poorly visualized with clinical imaging, hampering efforts to use diagnostic imaging to predict failure and enable intervention. Introducing nanoparticle contrast agents into polymers is a potential method for creating radiopaque materials that can be monitored via computed tomography. However, the properties of composites may be altered with nanoparticle addition, jeopardizing device functionality. Thus, the material and biomechanical responses of model nanoparticle‐doped biomedical devices (phantoms), created from 0–40 wt% tantalum oxide (TaOx) nanoparticles in polycaprolactone and poly(lactide‐co‐glycolide) 85:15 and 50:50, representing non, slow, and fast degrading systems, respectively, are investigated. Phantoms degrade over 20 weeks in vitro in simulated physiological environments: healthy tissue (pH 7.4), inflammation (pH 6.5), and lysosomal conditions (pH 5.5), while radiopacity, structural stability, mechanical strength, and mass loss are monitored. The polymer matrix determines overall degradation kinetics, which increases with lower pH and higher TaOxcontent. Importantly, all radiopaque phantoms could be monitored for a full 20 weeks. Phantoms implanted in vivo and serially imaged demonstrate similar results. An optimal range of 5–20 wt% TaOxnanoparticles balances radiopacity requirements with implant properties, facilitating next‐generation biomedical devices.
8 April 2011 in Angewandte Chemie International Edition