Brij M. Moudgil

Nanoparticles as contrast agents for in-vivo bioimaging: current status and future perspectives

Nanoparticle-based contrast agents are quickly becoming valuable and potentially transformative tools for enhancing medical diagnostics for a wide range of in-vivo imaging modalities. Compared with conventional molecular-scale contrast agents, nanoparticles (NPs) promise improved abilities for in-vivo detection and potentially enhanced targeting efficiencies through longer engineered circulation times, designed clearance pathways, and multimeric binding capacities. However, NP contrast agents are not without issues. Difficulties in minimizing batch-to-batch variations and problems with identifying and characterizing key physicochemical properties that define the in-vivo fate and transport of NPs are significant barriers to the introduction of new NP materials as clinical contrast agents. This manuscript reviews the development and application of nanoparticles and their future potential to advance current and emerging clinical bioimaging techniques. A focus is placed on the application of solid, phase-separated materials, for example metals and metal oxides, and their specific application as contrast agents for in-vivo near-infrared fluorescence (NIRF) imaging, magnetic resonance imaging (MRI), positron emission tomography (PET), computed tomography (CT), ultrasound (US), and photoacoustic imaging (PAI). Clinical and preclinical applications of NPs are identified for a broad spectrum of imaging applications, with commentaries on the future promise of these materials. Emerging technologies, for example multifunctional and theranostic NPs, and their potential for clinical advances are also discussed.

Rapid and effective labeling of brain tissue using TAT-conjugated CdS∶Mn/ZnS quantum dots

TAT (a cell penetrating peptide)-conjugated CdSratioMn/ZnS quantum dots (Qdots), intra-arterially delivered to a rat brain, rapidly (within a few minutes) labeled the brain tissue without manipulating the blood-brain-barrier (BBB). Qdot loading was sufficiently high that it allowed a gross fluorescent visualization of the whole rat brain using a low power hand-held UV lamp. Histological data clearly showed that TAT-conjugated Qdots migrated beyond the endothelial cell line and reached the brain parenchyma. Qdots without TAT did not label the brain tissue confirming the fact that TAT peptide was necessary to overcome the BBB. The present study clearly demonstrated the possibility of delivering a large amount of Qdot-based imaging agents to the brain tissue.

Characterization of the size, shape, and state of dispersion of nanoparticles for toxicological studies

This paper describes the issues relating to the measurement of nanoparticle size, shape and dispersion when evaluating the toxicity of nanoparticles. Complete characterization of these materials includes much more than size, size distribution and shape; nonetheless, these attributes are usually the essential foundation. The measurement of particle size, particularly at scales of 100 nm or less, can be challenging under the best of conditions. Measurements that are routine in the laboratory setting become even more difficult when made under the physiological conditions relevant to toxicity studies, where the environment of the particles can be quite complex. Passive and active cellular responses, as well as the presence of a variety of nano-scale biological structures, often complicate the collection and interpretation of size and shape data. In this paper, we highlight several of the common issues faced when characterizing nanoparticles for toxicity testing and suggest general protocols to address these problems.

Capillary forces between surfaces with nanoscale roughness

The flow and adhesion behavior of fine powders (approx. less than 10 microm) is significantly affected by the magnitude of attractive interparticle forces. Hence, the relative humidity and magnitude of capillary forces are critical parameters in the processing of these materials. In this investigation, approximate theoretical formulae are developed to predict the magnitude and onset of capillary adhesion between a smooth adhering particle and a surface with roughness on the nanometer scale. Experimental adhesion values between a variety of surfaces are measured via atomic force microscopy and are found to validate theoretical predictions.

Gold nanoparticles as a contrast agent for in vivo tumor imaging with photoacoustic tomography

Photoacoustic tomography (PAT) is a rapidly emerging non-invasive imaging technology that integrates the merits of high optical contrast with high ultrasound resolution. The ability to quantitatively and non-invasively image nanoparticles has important implications for the development of nanoparticles as in vivo cancer diagnostic and therapeutic agents. In this study, the ability of systemically administered poly(ethylene glycol)-coated (PEGylated) gold nanoparticles as a contrast agent for in vivo tumor imaging with PAT has been evaluated. We demonstrate that gold nanoparticles (20 and 50 nm) have high photoacoustic contrast as compared to mouse tissue ex vivo. Gold nanoparticles can be visualized in mice in vivo following subcutaneous administration using PAT. Following intravenous administration of PEGylated gold nanoparticles to tumor-bearing mice, accumulation of gold nanoparticles in tumors can be effectively imaged with PAT. With gold nanoparticles as a contrast agent, PAT has important potential applications in the image guided therapy of superficial tumors such as breast cancer, melanoma and Merkel cell carcinoma.

Effect of Particle Size of Chemical Mechanical Polishing Slurries for Enhanced Polishing with Minimal Defects

In this study the effects of oversize particle contamination in chemical mechanical polishing (CMP) slurries were investigated on the silica CMP process. The limits of light scattering technique were established in detecting coarse particles in a commercial silica CMP slurry using two different methods. The detection limits were set by observing the shift in particle size distribution curve or by the appearance of an additional peak in the particle size distribution curve of the baseline slurry when a known amount of coarser particles were added to it. Simultaneously, polishing tests were conducted by spiking the base slurry with coarser sol‐gel silica particles at the established detection limits. It was observed that the contamination of larger particles not only created surface damage but also changed the material removal rate. The mechanism of polishing in the presence of larger size particles is discussed as a function of particle size and concentration.

TAT conjugated, FITC doped silica nanoparticles for bioimaging applications

Water-in-oil (w/o) microemulsion synthesis of 70 nm size monodisperse TAT (a cell penetrating peptide, CPP) conjugated, FITC (fluorescein isothiocyanate) doped silica nanoparticles (TAT-FSNPs) is reported; human lung adenocarcinoma (A549) cells (in vitro) and rat brain tissue (in vivo) were successfully labeled using TAT-FSNPs.

Fluorescent Nanoparticle Probes for Cancer Imaging

Optical imaging technique has strong potential for sensitive cancer diagnosis, particularly at the early stage of cancer development. This is a sensitive, non-invasive, non-ionizing (clinically safe) and relatively inexpensive technique. Cancer imaging with optical technique however greatly relies upon the use of sensitive and stable optical probes. Unlike the traditional organic fluorescent probes, fluorescent nanoparticle probes such as dye-doped nanoparticles and quantum dots (Qdots) are bright and photostable. Fluorescent nanoparticle probes are shown to be very effective for sensitive cancer imaging with greater success in the cellular level. However, cancer imaging in an in vivo setup has been recently realized. There are several challenges in developing fluorescent nanoparticle probes for in vivo cancer imaging applications. In this review, we will discuss various aspects of nanoparticle design, synthesis, surface functionalization for bioconjugation and cancer cell targeting. A brief overview of in vivo cancer imaging with Qdots will also be presented.

Excimer laser deposition of hydroxyapatite thin films

We have demonstrated a new and simple in situ method to fabricate adherent and dense hydroxyapatite (HA) coatings at relatively low deposition temperatures (500-600 degrees C). Under optimum processing conditions, the HA coatings possess a nominal Ca:P ratio of 1.65 and exhibit a fully crystalline single-phase structure. This deposition technique is based on the application of a pulsed excimer laser (wavelength lambda = 248 nm, pulse duration tau = 25 x 10(-9) s) to ablate a dense stoichiometric HA target. The HA target was prepared by standard ceramic coprecipitation techniques followed by cold pressing and further sintering at 1200 degrees C in air. High substrate temperatures (> or = 600 degrees C) during film deposition led to phosphorus deficient coatings because of re-evaporation of phosphorus during the deposition process. The stabilization of various calcium and phosphorus phases in the film was controlled by a number of process parameters such as substrate temperature, chamber pressure and presence of water vapour in the chamber. This is particularly advantageous for production of HA coatings, since it is known that HA decomposes at high temperatures due to the uncertainty in the starting material stoichiometry. Rutherford backscattering spectrometry, energy dispersive X-ray analysis, transmission electron microscopy, scanning electron microscopy and X-ray diffraction techniques were employed to determine the structure-processing relationships. Qualitative scratch measurements were conducted to determine the adhesion strength of the films.

Influence of Suwannee River humic acid on particle properties and toxicity of silver nanoparticles

Adsorption of natural organic matter (NOM) on nanoparticles can have dramatic impacts on particle dispersion resulting in altered fate and transport as well as bioavailability and toxicity. In this study, the adsorption of Suwannee River humic acid (SRHA) on silver nanoparticles (nano-Ag) was determined and showed a Langmuir adsorption at pH 7 with an adsorption maximum of 28.6 mg g(-1) nano-Ag. It was also revealed that addition of <10 mg L(-1) total organic carbon (TOC) increased the total Ag content suspended in the aquatic system, likely due to increased dispersion. Total silver content decreased with concentrations of NOM greater than 10mg TOCL(-1) indicating an increase in nanoparticle agglomeration and settling above this concentration. However, SRHA did not have any significant effect on the equilibrium concentration of ionic Ag dissolved in solution. Exposure of Daphnia to nano-Ag particles (50 μg L(-1) and pH 7) produced a linear decrease in toxicity with increasing NOM. These results clearly indicate the importance of water chemistry on the fate and toxicity of nanoparticulates.