Redox-active self-assembled monolayers (SAMs) provide an excellent platform for investigating electron transfer kinetics. Using a well-defined bridge, a redox center can be positioned at a fixed distance from the electrode and electron transfer kinetics probed using a variety of electrochemical techniques. Cyclic voltammetry, AC voltammetry, electrochemical impedance spectroscopy, and chronoamperometry are most commonly used to determine the rate of electron transfer of redoxactivated SAMs. A variety of redox species have been attached to SAMs, and include transition metal complexes (e.g., ferrocene, ruthenium pentaammine, osmium bisbipyridine, metal clusters) and organic molecules (e.g., galvinol, C 60 ). SAMs offer an ideal environment to study the outer-sphere interactions of redox species. The composition and integrity of the monolayer and the electrode material influence the electron transfer kinetics and can be investigated using electrochemical methods. Theoretical models have been developed for investigating SAM structure. This review discusses methods and monolayer compositions for electrochemical measurements of redox-active SAMs.

We have developed a modular architecture for preparing high-relaxivity multiplexed probes utilizing click chemistry. Our system incorporates azide bearing Gd(III) chelates and a trialkyne scaffold with a functional group for subsequent modification. In optimizing the relaxivity of this new complex we undertook a study of the linker length between a chelate and the scaffold to determine its effect on relaxivity. The results show a strong dependence on flexibility between the individual chelates and the scaffold with decreasing linker length leading to significant increases in relaxivity. Nuclear magnetic resonance dispersion (NMRD) spectra were obtained to confirm a tenfold increase in the rotational correlation time from 0.049 ns to 0.60 ns at 310 K. We have additionally obtained a crystal structure demonstrating that modification with an azide does not impact the coordination of the lanthanide. The resulting multinuclear center has a 500% increase in per Gd (or ionic) relaxivity at 1.41 T versus small molecule contrast agents and a 170% increase in relaxivity at 9.4 T.

Ultrasmall (3, 4, 5, and 6 nm), water-soluble Fe3O4 magnetic nanoparticles were synthesized in diethylene glycol (DEG) via a facile one-pot reaction. Hydrodynamic size and relaxation time measurements did not show particle aggregation when Fe3O4 nanoparticles were dispersed in phosphate buffered saline, fetal bovine serum, or calf bovine serum for 1 week. Furthermore, the new Fe3O4 nanoparticles tolerated high salt concentrations (≤1 M NaCl) and a wide pH range from 5 to 11. Surface modification of the nanoparticles with poly(ethylene glycol) bis(carboxymethyl) ether (HOOC-PEG-COOH, 600 g/mol) was accomplished through a ligand-exchange reaction. The effects of PEG modification on magnetization and relaxivity of the Fe3O4 nanoparticles were investigated, and the results indicate that the increase in transverse relaxivity after PEG modification may be due to the increased volume of slowly diffusing water surrounding each nanoparticle. In vitro experiments showed that the DEG- and PEG-coated Fe3O4 nanoparticles have little effect on NIH/3T3 cell viability.

The kinetic and thermodynamic ligand exchange dynamics are important considerations in the rational design of metal-based therapeutics and therefore, require detailed investigation. Co(III) Schiff base complex derivatives of bis(acetylacetone) ethylenediimine [acacen] have been found to be potent enzyme and transcription factor inhibitors. These complexes undergo solution exchange of labile axial ligands. Upon dissociation, Co(III) irreversibly interacts with specific histidine residues of a protein, that alters structure and causes inhibition. In order to guide the rational design of next generation agents, understanding the mechanism and dynamics of the ligand exchange process is essential. To investigate the lability, pH stability, and axial ligand exchange of these complexes in the absence of proteins, the pD- and temperature-dependent axial ligand substitution dynamics of a series of N-heterocyclic [Co(acacen)(X)2]+ complexes [where X = 2-methylimidazole (2MeIm), 4-methylimidazole (4MeIm), ammine (NH3), N-methylimidazole (NMeIm), and pyridine (Py)] were prepared and characterized by NMR spectroscopy. The pD stability was shown to be closely related to the nature of the axial ligand with the following trend toward aquation: 2MeIm > NH3 >> 4MeIm > Py > Im > NMeIm. Reaction of each [Co(III)(acacen)(X)2]+ derivative with 4MeIm showed formation of a mixed ligand Co(III) intermediate via a dissociative ligand exchange mechanism. The stability of the mixed ligand adduct was directly correlated to the pD-dependent stability of the starting Co(III) Schiff base with respect to [Co(acacen)(4MeIm)2]+. Crystal structure analysis of the [Co(acacen)(X)2]+ derivatives confirmed the trends in stability observed by NMR spectroscopy. Bond distances between the Co(III) and the axial nitrogen atoms were longest in the 2MeIm derivative as a result of distortion in the planar tetradentate ligand, and this was directly correlated to axial ligand lability and propensity toward exchange.

A one-pot reaction process was developed to synthesize highly dispersible, superparamagnetic Fe3O4 nanoflowers; the potential of these nanoflowers as MRI contrast agents was investigated.

We report a mechanistic investigation of an isomeric series of β-galactosidase-activated magnetic resonance contrast agents. Our strategy focuses on the synthesis of macrocyclic caged-complexes that coordinatively saturate a chelated lanthanide. Enzyme cleavage of the complex results in an open coordination site available for water that creates a detectable MR contrast agent. The complexes consist of a DO3A Gd(III) chelator modified with a galactopyranose at the N-10 position of the macrocycle. We observed significant differences in relaxometric properties and coordination geometry that can be correlated to subtle variations of the linker between the macrocycle and the galactopyranose. After synthesis and purification of the R, S, and racemic mixtures of complexes 1 and 3 and measurement of the hydration number, water residence lifetime, and longitudinal relaxation rates, we propose mechanisms for water exclusion from the lanthanide in the precleavage state. While the stereochemistry of the linker does not influence the agents' properties, the mechanism of water exclusion for each isomer is significantly influenced by the position of modification. Data for one series with a methyl group substituted on the sugar-macrocycle linker at the R-position suggests a steric mechanism where the galactopyranose sugar blocks water from the Gd(III) center. In contrast, our observations for a second series with methyl substitution at the β position of the sugar-macrocycle linker are consistent with a mechanism in which a bidentate anion occupies two available coordination sites of Gd(III) in the precleavage state.

Nanomaterials with mixed composition, in particular magnetic spinel ferrites, are emerging as efficient contrast agents for magnetic resonance imaging (MRI). Many factors, including size, composition, atomic structure, and surface properties are crucial in the design of such nanoparticle-based probes due to their influence on the magnetic properties. Silica-coated iron oxide (IO-SiO2) and cobalt ferrite (CoIO-SiO2) nanoparticles were synthesized using standard high temperature thermal decomposition and base-catalyzed water-in-oil microemulsion techniques. Under neutral aqueous conditions, it was found that 50–75% of the cobalt content in the CoIO-SiO2 nanoparticles leached out of the core structure. Leaching caused a 7.2-fold increase in longitudinal relaxivity and an increase in the saturation magnetization from ~48 emu/g core to ~65 emu/g core. X-ray absorption fine structure studies confirmed that the atomic structure of the ferrite core was altered following leaching, while TEM and DLS confirmed that the morphology and size of the nanoparticle remained unchanged. The CoIO-SiO2 nanoparticles converted from a partially inverted spinel cation arrangement (unleached state) to an inverse spinel arrangement (leached state). The control IO-SiO2 nanoparticles remained stable with no change in structure and negligible changes in magnetic behavior. This detailed analysis highlights how important understanding the properties of nanomaterials is in the development of reliable agents for diagnostic and therapeutic applications.

Oligomers of the Aβ42 peptide are significant neurotoxins linked to Alzheimer’s Disease (AD). Histidine (His) residues present at the N-terminus of Aβ42 are believed to influence toxicity by either serving as metal-ion binding sites (that promote oligomerization and oxidative damage) or facilitating synaptic binding. Transition metal complexes that bind to these residues and modulate Aβ toxicity have emerged as therapeutic candidates. Cobalt(III) Schiff base complexes (Co(III)-sb) were evaluated for their ability to interact with Aβ peptides. HPLC-MS, NMR, fluorescence, and DFT studies demonstrated that Co(III)-sb complexes could interact with the His residues in a truncated Aβ16 peptide representing the Aβ42 N-terminus. Coordination of Co(III)-sb complexes altered the structure of Aβ42 peptides and promoted the formation of large soluble oligomers. Interestingly, this structural perturbation of Aβ correlated to reduced synaptic binding to hippocampal neurons. These results demonstrate the promise of Co(III)-sb complexes in anti-AD therapeutic approaches.