Brian A. Larsen

Renal Inflammation: Targeted Iron Oxide Nanoparticles for Molecular MR Imaging in Mice

PURPOSE To determine the feasibility of T2-weighted magnetic resonance (MR) imaging in the noninvasive quantification of renal inflammation by using superparamagnetic iron oxide (SPIO) nanoparticles targeted to tissue-bound C3 activation fragments in a mouse model of lupus nephritis. MATERIALS AND METHODS All animal procedures were approved by the University of Colorado-Denver animal care and use committee. SPIO nanoparticles were encapsulated by using amine-functionalized phospholipids. A recombinant protein containing the C3d-binding region of complement receptor type 2 (CR2) was then conjugated to the surface of the SPIO nanoparticle. Five MRL/lpr mice (a model of lupus nephritis) and six C57BL/6 wild-type mice were assessed with T2-weighted MR imaging at baseline and after SPIO injection. The same five MRL/lpr mice and three C57BL/6 mice also underwent MR imaging after injection of CR2-targeted SPIO. A series of T2-weighted pulses with 16 echo times was used to enable precise T2 mapping and calculation of T2 relaxation times in the cortex and outer and inner medulla of the kidneys, as well as in the spleen, muscle, and fat. The effects of treatment and animal genotype on T2 relaxation times were analyzed with repeated-measures analysis of variance. RESULTS At baseline, the T2-weighted signal intensity in the kidneys of MRL/lpr mice was higher than that in the kidneys of wild-type mice. Injection of untargeted SPIO did not alter the T2-weighted signal in the kidneys in either strain of mice. Injection of CR2-targeted SPIO in MRL/lpr mice, however, caused a significant accumulation of targeted iron oxide with a subsequent decrease in T2 relaxation times in the cortex and outer and inner medulla of the kidneys. No changes in T2 relaxation time were observed in the wild-type mice after injection of targeted SPIO. CONCLUSION Injection of CR2-conjugated SPIO caused a significant reduction in T2-weighted MR imaging signal and T2 relaxation time in nephritic kidneys.

Detection of glomerular complement C3 fragments by magnetic resonance imaging in murine lupus nephritis

One of the challenges of treating patients with glomerulonephritis is to accurately assess disease activity. As renal biopsies are routinely stained for deposits of C3 activation fragments and glomerular C3 deposits are found in most forms of glomerulonephritis, we sought to determine whether a relatively noninvasive measure of C3 fragment deposition in the kidney can serve as a good biomarker of disease onset and severity. We recently developed a magnetic resonance imaging (MRI)-based method of detecting glomerular C3 and used this to track the progression of renal disease in the MRL/lpr mouse model of lupus nephritis using superparamagnetic iron oxide nanoparticles conjugated to complement receptor type 2 as a targeting agent. Quantitative immunofluorescence showed that glomerular C3b/iC3b/C3d deposition progressively increased with disease activity, a finding replicated by the T2-weighted MRI. The T2 relaxation times decreased with disease activity in the cortex and medulla of the MRL/lpr but not in MRL/Mpj control mice. Thus, MRI contrast agents targeted to glomerular C3 fragments can be used to noninvasively monitor disease activity in glomerulonephritis. As therapeutic complement inhibitors are used in patients with renal disease, this method, should it become feasible in humans, may identify those likely to benefit from complement inhibition.

Preparation of freestanding germanium nanocrystals by ultrasonic aerosol pyrolysis

This letter reports a synthetic route adaptable for the continuous, large-scale production of germanium (Ge) nanocrystals for emerging electronic and optoelectronic applications. Using an ultrasonic aerosol pyrolysis approach, diamond cubic Ge nanocrystals with dense, spherical morphologies and sizes ranging from 3to14nm are synthesized at 700°C from an ultrasonically generated aerosol of tetrapropylgermane (TPG) precursor and toluene solvent. The ultimate crystal size demonstrates a near linear relationship within the range of TPG concentrations investigated, while the shape of the measured size distributions predicts multiple particle formation mechanisms during aerosol decomposition and condensation.

Controlling nanoparticle aggregation in colloidal microwave absorbers via interface chemistry

Interface chemistry can be implemented to modulate the aggregation and dispersion of nanoparticles in a colloidal solution. In this experimental study, we demonstrate the controlled aggregation of superparamagnetic magnetite nanoparticles in organic and aqueous solutions. With decrease in solution pH, individual nanoparticles (12-14 nm) reproducibly cluster to form ~52 nm monodisperse aggregates in toluene. Spin-spin (T2) proton relaxation measurements of the micellated clusters before and after aggregation show a change in the molar relaxation rate from 303 sec-1mol-1 to 368 sec-1mol-1 for individual and clustered nanoparticles, respectively. DNA-mediated aggregation of micellated nanoparticles in the colloidal solution is also demonstrated where the number of single-stranded DNA per particle determines the ultimate size of the nanoparticle aggregate.

Phospholipid Encapsulation and Surface Functionalization of Superparamagnetic Iron Oxide Nanoparticles for Molecular Magnetic Resonance Imaging: Effects on Spin-Spin Proton Relaxation

Superparamagnetic iron oxide (SPIO) nanoparticles are prevalent as nanoprobes for molecular magnetic resonance imaging (MRI), providing negative contrast by locally affecting the spin-spin (T2) proton relaxation of water. SPIO nanoparticles are typically Fe3O4 nanocrystals and are commonly used as a negative MRI contrast agent, implementing various surface functionalization techniques to provide molecular targeting to biological macromolecules. The authors recently demonstrated molecular MRI (Figure 1) of epidermal growth factor receptor (EGFR), an extensively studied oncoprotein, in human prostate and head-and-neck cancer cell lines using monoclonal antibodies covalently conjugated to phospholipid micelle encapsulated 12 nm single crystalline SPIO nanoparticles, demonstrating molecular targeting capabilities via surface functionalization [1].© 2007 ASME