Randy P. Carney

A general mechanism for intracellular toxicity of metal-containing nanoparticles

We demonstrate a general mechanism for the toxicity induced by metal-containing NPs, named “lysosome-enhanced Trojan horse effect”, which provides design rules to engineer safer NPs.

Effect of Particle Diameter and Surface Composition on the Spontaneous Fusion of Monolayer-Protected Gold Nanoparticles with Lipid Bilayers

Anionic, monolayer-protected gold nanoparticles (AuNPs) have been shown to nondisruptively penetrate cellular membranes. Here, we show that a critical first step in the penetration process is potentially the fusion of such AuNPs with lipid bilayers. Free energy calculations, experiments on unilamellar and multilamellar vesicles, and cell studies all support this hypothesis. Furthermore, we show that fusion is only favorable for AuNPs with core diameters below a critical size that depends on the monolayer composition.

Synthesis and Characterization of Janus Gold Nanoparticles

When gold nanoparticles are coated with binary mixtures of dislike ligand molecules, separation in the ligand shell occurs; if the particles are smaller than a threshold size the separation is solely enthalpy driven leading to the spontaneous formation of Janus particles.

Dynamic Cellular Uptake of Mixed-Monolayer Protected Nanoparticles

Nanoparticles (NPs) are gaining increasing attention for potential application in medicine; consequently, studying their interaction with cells is of central importance. We found that both ligand arrangement and composition on gold nanoparticles play a crucial role in their cellular internalization. In our previous investigation, we showed that 66-34OT nanoparticles coated with stripe-like domains of hydrophobic (octanethiol, OT, 34%) and hydrophilic (11-mercaptoundecane sulfonate, MUS, 66%) ligands permeated through the cellular lipid bilayer via passive diffusion, in addition to endo-/pino-cytosis. Here, we show an analysis of NP internalization by DC2.4, 3T3, and HeLa cells at two temperatures and multiple time points. We study four NPs that differ in their surface structures and ligand compositions and report on their cellular internalization by intracellular fluorescence quantification. Using confocal laser scanning microscopy we have found that all three cell types internalize the 66-34OT NPs more than particles coated only with MUS, or particles coated with a very similar coating but lacking any detectable ligand shell structure, or ‘striped’ particles but with a different composition (34-66OT) at multiple data points.

Colloidal stability of self-assembled monolayer-coated gold nanoparticles: the effects of surface compositional and structural heterogeneity.

Surface heterogeneity plays an important role in controlling colloidal phenomena. This study investigated the self-aggregation and bacterial adsorption of self-assembled monolayer coated gold nanoparticles (AuNPs) with different surface compositional and structural heterogeneity. Evaluation was performed on AuNPs coated with (1) one ligand with charged terminals (MUS), (2) two homogeneously distributed ligands with respectively charged and nonpolar terminals (brOT) and (3) two ligands with respectively charged and nonpolar terminals with stripe-like distribution (OT). The brOT particles have less negative electrophoretic mobility (EPM) values, smaller critical coagulation concentration (CCC) and larger adsorption rate on Escherichia coli than that of AuNPs with homogeneously charged groups, in good agreement with DLVO predictions. Although the ligand composition on the surface of AuNPs is the same, OT particles have less negative EPM values and faster rate of bacterial adsorption, but much larger CCC compared to brOT. The deviation of OT particles from brOT and MUS in their self-aggregation behavior reflects the effects of surface heterogeneity on electrical double layer structures at the interface. Results from the present study demonstrated that, besides chemical composition, organization of ligands on particle surface is important in determining their colloidal stability.

Erythrocyte incubation as a method for free-dye presence determination in fluorescently labeled nanoparticles.

The field of nanotheranostics encompasses the integration of nanosized carriers in cancer imaging, diagnosis, and therapy. The use of nanomedicines for theranostic application typically depends on direct visualization of the nanocarriers. Normally fluorescent probes are attached to nanocarriers for biodistribution measurement through fluorescence imaging. However continued, noninvasive assurance that the fluorescent probe remains bound to the carrier has proven elusive. Mature erythrocytes, also known as red blood cells, are incapable of endocytosis. As a consequence, when incubated with fluorescently labeled particles, they do not show any signal coming from the membrane or the cytoplasm. Yet, these cells readily take up free BODIPY fluorescent dyes into their membranes. Here we show that incubation of nanoparticles with erythrocytes is a rapid and reliable method for the detection of unbound dye present within a nanoparticle sample, as the detection of a fluorescent signal coming from the cells can only be due to unbound dye present in the sample. We test the method on both sulfonate and PEG terminated gold nanoparticles, and we determine the minimum concentration of detectable dye for a specific gold nanoparticle sample.

Superparamagnetic Nanoparticles as High Efficiency Magnetic Resonance Imaging T2 Contrast Agent

Nanoparticle-based magnetic resonance imaging T2 negative agents are of great interest, and much effort is devoted to increasing cell-loading capability while maintaining low cytotoxicity. Herein, two classes of mixed-ligand protected magnetic-responsive, bimetallic gold/iron nanoparticles (Au/Fe NPs) synthesized by a two-step method are presented. Their structure, surface composition, and magnetic properties are characterized. The two classes of sulfonated Au/Fe NPs, with an average diameter of 4 nm, have an average atomic ratio of Au to Fe equal to 7 or 8, which enables the Au/Fe NPs to be superparamagnetic with a blocking temperature of 56 K and 96 K. Furthermore, preliminary cellular studies reveal that both Au/Fe NPs show very limited toxicity. MRI phantom experiments show that r2/r1 ratio of Au/Fe NPs is as high as 670, leading to a 66% reduction in T2 relaxation time. These nanoparticles provide great versatility and potential for nanoparticle-based diagnostics and therapeutic applications and as imaging contrast agents.

A silica-based magnetic platform decorated with mixed ligand gold nanoparticles: a recyclable catalyst for esterification reactions

A novel and convenient synthetic strategy for the preparation of magnetically responsive silica nanospheres decorated with mixed ligand protected gold nanoparticles is described. Gold nanoparticles are attached to the silica surface via stable amide bond formation. The hierarchical nanospheres show promising results as reusable and efficient catalysts for esterification reactions and they can be recovered through a simple magnetic separation.

Isolation and Characterization of Monodisperse Core Shell Nanoparticle Fractions

Monodispersity is a key property to control the self-assembly of colloidal particles, and is typically reached after fine-tuning of the synthesis conditions. Monodisperse particle fractions can also be separated from polydisperse suspensions via ultracentrifugation. This paper demonstrates the capability of isolating and characterizing suspensions of core-shell iron oxide-polymer nanoparticles with extremely low polydispersity (p < 0.01) and, thus, of complementing nanoparticle synthetic approaches in the pursuit of highly monodisperse materials.

Deciphering the metabolic role of AMPK in cancer multi-drug resistance

Multi-drug resistance (MDR) is a curious bottleneck in cancer research and chemotherapy, whereby some cells rapidly adapt to the tumor microenvironment via a myriad of heterogeneous metabolic activities. Despite being a major impediment to treatment, there is a silver lining: control over metabolic regulation could be an effective approach to overcome or correct resistance pathways. In this critical review, we comprehensively and carefully curated and analyzed large networks of previously identified proteins associated with metabolic adaptation in MDR. We employed data and text mining to study and categorize more than 600 studies in PubMed, with particular focus on AMPK, a central and fundamental modulator in the energy metabolism network that has been specifically implicated in cancer MDR pathways. We have identified one protein set of metabolic adaptations with 137 members closely related to cancer MDR processes, and a second protein set with 165 members derived from AMPK-based networks, with 28 proteins found at the intersection between the two sets. Furthermore, according to genomics analysis of the cancer genome atlas (TCGA) provisional data, the highest alteration frequency (80.0%) of the genes encoding the intersected proteins (28 proteins), ranked three cancer types with quite remarkable significance across 166 studies. The hierarchical relationships of the entire identified gene and protein networks indicate broad correlations in AMPK-mediated metabolic regulation pathways, which we use decipher and depict the metabolic roles of AMPK and demonstrate the potential of metabolic control for therapeutic intervention in MDR.