Selectively permeable biological membranes composed of lipophilic barriers inspire the design of biomimetic carrier-mediated membranes for aqueous solute separation. This work imparts selective permeability to lipid-filled pores of silica thin film composite membranes using carrier molecules that reside in the lipophilic self-assemblies. The lipids confined inside the pores of silica are proven to be a more effective barrier than bilayers formed on the porous surface through vesicle fusion, which is critical for quantifying the function of an immobilized carrier. The ability of a lipophilic carrier embedded in the lipid bilayer to reversibly bind the target solute and transport it through the membrane is demonstrated. Through the functionalization of the silica surface with enzymes, enzymatic catalysis and biomimetic separations can be combined on this nanostructured composite platform. The successful development of biomimetic nanocomposite membrane can provide for efficient dilute aqueous solute upgrading or separations using engineered carrier/catalyst/support systems. While the carrier-mediated biomimetic membranes hold great potential, fully understanding of the transport processes in composite synthetic membranes is essential for improve the membrane performance. Electrochemical impedance spectroscopy (EIS) technique is demonstrated to be a useful tool for characterizing the thin film pore accessibility. Furthermore, the effect of lipid bilayer preparation methods on the silica thin film (in the form of pore enveloping, pore filling) on ion transport is explored, as a lipid bilayer with high electrically insulation is essential for detecting activity of proteins or biomimetic carriers in the bilayer. This study provides insights for making better barriers on mesoporous support for carrier-mediated membrane separation process. Porous silica nanoparticles (pSNPs) with pore sizes appropriate for biomolecule loading are potential for encapsulating dsRNA within the pores to achieve effective delivery of dsRNA to insects for RNA interference (RNAi). The mobility of dsRNA in the nanopores of the pSNPs is expected to have a functional effect on delivery of dsRNA to insects. The importance of pores to a mobile dsRNA network is demonstrated by the lack of measurable mobility for both lengths of RNA on nonporous materials. In addition, when the dsRNA could not penetrate the pores, dsRNA mobility is also not measurable at the surface of the particle. Thus, the pores seem to serve as a “sink” in providing a mobile network of dsRNA on the surface of the particle. This work successfully demonstrates the loading of RNA on functionalized pSNPs and identified factors that affects RNA loading and releasing, which provides basis for the delivery of RNA-loaded silica particles in vivo.

The elimination of drugs from the body is in many cases performed by the liver. Much could be gained if an accurate prediction of this process could be made early in the development of new drugs. However, for the elimination to occur, the drug molecule needs first to get inside the liver cell. Disposition is the expression used to encapsulate both elimination and distribution. This thesis presents novel approaches and models based on simple in vitro systems for the investigation of processes involved in the hepatic drug disposition. An approach to the estimation of enzyme kinetics based on substrate depletion data from cell fractions was thoroughly evaluated through experiments and simulations. The results that it provided were confirmed to be accurate and robust. In addition, a new experimental setup suitable for a screening environment, i.e., for a reduced number of samples, was generated through optimal experimental design. The optimization suggested that sampling at late time points over a wide range of concentration was the most advantageous. A model, based on data from primary hepatocytes in suspension, for the investigation of cellular disposition of metabolized drugs was developed. Information on the relative importance of metabolism and membrane protein related distribution was obtained by analysis of changes in the kinetics by specific inhibition of the various processes. The model was evaluated by comparing the results to those obtained from an in vivo study analyzed with an especially constructed mechanistic PBPK model. These investigations showed that the suggested model produced good predictions of the relative importance of metabolism and carrier mediated membrane transport for hepatic disposition. In conclusion, new approaches for the investigation of processes involved in hepatic disposition were developed. These methods were shown to be robust and increased the output of information from already commonly implemented in vitro systems.

Membrane transport processes underlie many purification technologies. The efficiency of a membrane separation process depends upon material throughput (flux), and the degree to which the membrane discriminates amongst species in the feed stock (selectivity). In a supported liquid membrane, flux may be enhanced by carrier molecules, which act as catalysts of translocation. Carrier molecules also confer selectivity, via differential molecular recognition of the substances in the feed stock. The effect of electrical potential on the flux and selectivity of carrier-containing supported liquid membranes is not well documented. We elected to study the effect of electrical potential on supported liquid membranes containing valinomycin, a potassium ionophore, and a calixarene ester, a sodium ionophore. In these systems, the open circuit membrane potential could be made positive or negative by the choice of anion. With both of these carriers, we observed that selectivity for potassium or sodium salts was dependent on the open circuit membrane potential. To confirm that electrical potential was responsible for the observed selectivity variance, we applied a potential across the membrane using a potentiostat. The applied potential created conditions for carrier-mediated electrodialysis, where oxidation and reduction reactions on either side of the membrane act as the driving force for transmembrane flux of charged species. In chronoamperometry experiments, we found that selectivity for potassium or sodium ion was dependent on the applied electrical potential. Subject to some constraints, selectivity and flux could be controlled by the application of positive or negative electrical potentials. Linear sweep voltammetry experiments allowed for the rapid prediction of the potential that must be applied to achieve optimal selectivity. We also found that membrane potential measurements, as well as the magnitude of current that flows in chronoamperometry experiments, could be interpreted to predict Eisenman and Hofmeister sequences. These results are novel, and await a convincing theoretical justification. The results also suggest that a separation technology could be developed around the idea of modulating selectivity with electrical potential. In this regard, carrier-mediated electrodialysis may be suitable for the sequestration of toxic or radioactive heavy metals, and a large number of carrier molecules for metal ions are currently known. The technique may also be suitable for separating organic molecules, such as high-value chiral pharmaceuticals. Supported liquid membranes are a useful research tool, but industrial applications may require a more stable membrane architecture. / Graduate