Functionalized Gold Nanoparticles and Halogen Bonding Interactions Involving Fentanyl and Fentanyl Derivatives.

Fentanyl (FTN) and synthetic analogs of FTN continue to ravage populations across the globe, including in the United States where opioids are increasingly being used and abused and are causing a staggering and growing number of overdose deaths each year. This growing pandemic is worsened by the ease with which FTN can be derivatized into numerous derivatives. Understanding the chemical properties/behaviors of the FTN class of compounds is critical for developing effective chemical detection schemes using nanoparticles (NPs) to optimize important chemical interactions. Halogen bonding (XB) is an intermolecular interaction between a polarized halogen atom on a molecule and e--rich sites on another molecule, the latter of which is present at two or more sites on most fentanyl-type structures. Density functional theory (DFT) is used to identify these XB acceptor sites on different FTN derivatives. The high toxicity of these compounds necessitated a "fragmentation" strategy where smaller, non-toxic molecules resembling parts of the opioids acted as mimics of XB acceptor sites present on intact FTN and its derivatives. DFT of the fragments' interactions informed solution measurements of XB using 19F NMR titrations as well as electrochemical measurements of XB at self-assembled monolayer (SAM)-modified electrodes featuring XB donor ligands. Gold NPs, known as monolayer-protected clusters (MPCs), were also functionalized with strong XB donor ligands and assembled into films, and their interactions with FTN "fragments" were studied using voltammetry. Ultimately, spectroscopy and TEM analysis were combined to study whole-molecule FTN interactions with the functionalized MPCs in solution. The results suggested that the strongest XB interaction site on FTN, while common to most of the drug's derivatives, is not strong enough to induce NP-aggregation detection but may be better exploited in sensing schemes involving films.

The Role of Oxidation during the Synthesis of Silver-Glutathione Monolayer-Protected Clusters.

The synthesis of metal monolayer-protected clusters (MPCs) is still not well understood. It was recently shown that the mechanism of MPC formation involves sequential growth, wherein small MPCs form first and then grow into progressively larger sizes. The sequential growth model does not entirely explain all experimental observations, however. For example, the evolution of MPC product sizes is found to be a non-monotonic function of reaction kinetics, whereas the sequential growth model predicts monotonic behavior. Size evolution of MPCs is studied during synthetic reactions for a wide range of kinetics and it is found that all syntheses began with the sequential growth of MPCs but also found that growth transitioned to degradation if reduction kinetics are fast enough to give way to ambient oxidation. It is identified that MPCs can degrade via oxidation during syntheses and in a manner that is opposite to sequential growth, namely by forming smaller known MPC species from larger MPC species. This sequential degradation process therefore played an important role in determining final MPC products for reactions with fast reduction kinetics. Together, complementary oxidative and reductive processes provide a more complete description of MPC synthesis as well as new tools for controlling metal MPC synthesis.

Sequential Growth as a Mechanism of Silver-Glutathione Monolayer-Protected Cluster Formation.

Silver monolayer-protected clusters (MPCs) are an important new class of small metal nanoparticles with discrete sizes and unique properties that are eminently tunable; however, a fundamental understanding of the mechanisms of MPC formation is still lacking. Here, the basic mechanism by which silver-glutathione MPCs form is established by using real-time in situ optical measurements and ex situ solution-phase analyses to track MPC populations in the reaction mixture. These measurements identify that MPCs grow systematically, increasing in size sequentially as they transform from one known species to another, in contrast to existing models. In the new sequential growth model of MPC formation, the relative stability of each species in the series results in thermodynamic preferences for certain species as well as kinetic barriers to transformations between stable sizes. This model is shown to correctly predict the outcome of silver MPC synthetic reactions. Simple analytic expressions and simulations of rate equations are used to further validate the model and study its nature. The sequential growth model provides insights into how reactions may be directed, based on the interplay between relative MPC stabilities and reaction kinetics, providing tools for the synthesis of particular MPCs in high yield.

M4Au12Ag32(p-MBA)30 (M = Na, Cs) bimetallic monolayer-protected clusters: synthesis and structure.

Crystals of M4Au12Ag32(p-MBA)30 bimetallic monolayer-protected clusters (MPCs), where p-MBA is p-mercapto-benzoic acid and M+ is a counter-cation (M = Na, Cs) have been grown and their structure determined. The mol-ecular structure of triacontakis[(4-carboxylatophenyl)sulfanido]dodecagolddotriacontasilver, Au12Ag32(C7H5O2S)30 or C210H150Ag32Au12O60S30, exhib-its point group symmetry at 100 K. The overall diameter of the MPC is approximately 28 Å, while the diameter of the Au12Ag20 metallic core is 9 Å. The structure displays ligand bundling and inter-molecular hydrogen bonding, which gives rise to a framework structure with 52% solvent-filled void space. The positions of the M+ cations and the DMF solvent mol-ecules within the void space of the crystal could not be determined. Three out of the five crystallographically independent ligands in the asymmetric unit cell are disordered over two sets of sites. Comparisons are made to the all-silver M4Ag44(p-MBA)30 MPCs and to expectations based on density functional theory.

Dynamic Nature of Thiolate Monolayer in Au25(SR)18 Nanoclusters.

Thiolate monolayer, protecting a gold nanocluster, is responsible for its chemical behavior and interaction with the environment. Understanding the parameters that influence the stability and reactivity of the monolayer will enable its precise and controlled functionalization. Here we present a protocol for the investigation of the monolayer reactivity in Au25(SR)18 based on MALDI mass spectrometry and NMR spectroscopy. Thiol exchange reaction between cluster and thiol molecules has been investigated showing how this reaction is affected by several factors (stability of the thiols in solution, the affinity of the sulfur to the gold cluster, intermolecular interactions within the ligand layer, etc.). Furthermore, intercluster thiol exchange has been clarified to occur during collisions between particles without thiol release to the solution. In this reaction, the stability of the thiols in solution and the affinity of the sulfur to the gold for the two thiols do not affect the equilibrium position because for both thiols one S-Au bond is broken and one is formed within the cycle. Importantly, the rate of direct thiol exchange between clusters is comparable to that of the ligand exchange with free thiols. However, the thermodynamic driving force of the two reactions is different, since only the latter involves free thiol species.

Structure-function relationships affecting the sensing mechanism of monolayer-protected cluster doped xerogel amperometric glucose biosensors.

A systematic study of the structure-function relationships critical to understanding the sensing mechanism of 1st generation amperometric glucose biosensors with an embedded nanoparticle (NP) network is presented. Xerogel-based films featuring embedded glucose oxidase enzyme and doped with alkanethiolate-protected gold NPs, known as monolayer protected clusters (MPCs), exhibit significantly enhanced performance compared to analogous systems without NPs including higher sensitivity, faster response time, and extended linear/dynamic ranges. The proposed mechanism involves diffusion of the glucose to glucose oxidase within the xerogel, enzymatic reaction production of H2O2 with subsequent diffusion to the embedded network of MPCs where it is oxidized, an event immediately reported via fast electron transfer (ET) through the MPC system to the working electrode. Various aspects of the film construct and strategy are systematically probed using amperometry, voltammetry, and solid-state electronic conductivity measurements, including the effects of MPC peripheral chain length, MPC functionalization via place-exchange reaction, MPC core size, and the MPC density or concentration within the xerogel composite films. The collective results of these experiments support the proposed mechanism and identify interparticle spacing and the electronic communication through the MPC network is the most significant factor in the sensing scheme with the diffusional aspects of the mechanism that may be affected by film/MPC hydrophobicity and functionality (i.e., glucose and H2O2 diffusion) shown to be less substantial contributors to the overall enhanced performance. Understanding the structure-function relationships of effective sensing schemes allows for the employment of the strategy for future biosensor design toward clinically relevant targets.

Site-specific targeting of enterovirus capsid by functionalized monodisperse gold nanoclusters.

Development of precise protocols for accurate site-specific conjugation of monodisperse inorganic nanoparticles to biological material is one of the challenges in contemporary bionanoscience and nanomedicine. We report here a successful site-specific covalent conjugation of functionalized atomically monodisperse gold clusters with 1.5-nm metal cores to viral surfaces. Water-soluble Au102(para-mercaptobenzoic acid)44 clusters, functionalized by maleimide linkers to target cysteines of viral capsid proteins, were synthesized and conjugated to enteroviruses echovirus 1 and coxsackievirus B3. Quantitative analysis of transmission electron microscopy images and the known virus structures showed high affinity and mutual ordering of the bound gold clusters on the viral surface and a clear correlation between the clusters and the targeted cysteine sites close to the viral surface. Infectivity of the viruses was not compromised by loading of several tens of gold clusters per virus. These advances allow for future investigations of the structure-function relations of enteroviruses and enterovirus-related virus-like particles, including their entry mechanisms into cells and uncoating in cellular endosomes.