Pharmacokinetics of CuGTSM, a Novel Drug Candidate, in a Mouse Model of Menkes Disease.

PURPOSE: Menkes disease is a rare hereditary disease in which systemic deficiency of copper due to mutation of the ATP7A gene causes severe neurodegenerative disorders. The present parenteral drugs have limited efficacy, so there is a need for an efficacious drug that can be administered orally. This study focused on glyoxal-bis (N(4)-methylthiosemicarbazonato)-copper(II (CuGTSM), which has shown efficacy in macular mice, a murine model of Menkes disease, and examined its pharmacokinetics. In addition, nanosized CuGTSM (nCuGTSM) was prepared, and the effects of nanosizing on CuGTSM pharmacokinetics were investigated. METHODS: CuGTSM or nCuGTSM (10 mg/kg) was administered orally to male macular mice or C3H/HeNCrl mice (control), and plasma was obtained by serial blood sampling. Plasma concentrations of CuGTSM and GTSM were measured by LC-MS/MS and pharmacokinetic parameters were calculated. RESULTS: When CuGTSM was administered orally, CuGTSM and GTSM were both detected in the plasma of both mouse strains. When nCuGTSM was administered, the Cmax was markedly higher, and the mean residence time was longer than when CuGTSM was administered for both CuGTSM and GTSM in both mouse strains. With macular mice, the AUC ratio (GTSM/CuGTSM) was markedly higher and the plasma CuGTSM concentration was lower than with C3H/HeNCrl mice when either CuGTSM or nCuGTSM was administered. CONCLUSION: Absorption of orally administered CuGTSM was confirmed in macular mice, and the nano-formulation improved the absorption and retention of CuGTSM in the body. However, the plasma concentration of CuGTSM was lower in macular mice than in control mice, suggesting easier dissociation of CuGTSM.

Gold-coated silver nanowires for long lifetime AFM-TERS probes.

Tip-enhanced Raman scattering (TERS) microscopy is an advanced technique for investigation at the nanoscale because of its excellent properties, such as its label-free functionality, non-invasiveness, and ability to simultaneously provide topographic and chemical information. The probe plays a crucial role in TERS technique performance. Widely used AFM-TERS probes fabricated with metal deposition suffer from relatively low reproductivity as well as limited mapping and storage lifetime. To solve the reproducibility issue, silver nanowire (AgNW)-based TERS probes were developed, which, thanks to the high homogeneity of the liquid-phase synthesis of AgNW, can achieve high TERS performance with excellent probe reproductivity, but still present short lifetime due to probe oxidation. In this work, a simple Au coating method is proposed to overcome the limited lifetime and improve the performance of the AgNW-based TERS probe. For the Au-coating, different [Au]/[Ag] molar ratios were investigated. The TERS performance was evaluated in terms of changes in the enhancement factor (EF) and signal-to-noise ratio through multiple mappings and the storage lifetime in air. The Au-coated AgNWs exhibited higher EF than pristine AgNWs and galvanically replaced AgNWs with no remarkable difference between the two molar ratios tested. However, for longer scanning time and multiple mappings, the probes obtained with low Au concentration showed much longer-term stability and maintained a high EF. Furthermore, the Au-coated AgNW probes were found to possess a longer storage lifetime in air, allowing for long and multiple TERS mappings with one single probe.