Drug transport to the brain for the treatment of neurological diseases is a challenge due to impenetrable nature of the blood brain barrier (BBB). Intranasal (IN) drug administration is a non-invasive approach for rapid direct drug delivery from the nose to the central nervous system (CNS), thereby minimizing systemic exposure. The current study focuses on a strategy to enhance the delivery of the nucleoside drug gemcitabine (GEM) to the CNS via IN administration. Our approach took advantage of the fact that the BBB and olfactory epithelial tight junctions (TJs) share many proteins in common. We hypothesized that by transiently increasing the permeability of nasal epithelial tight junctions using the BBB permeabilizer papaverine (PV), we would increase the concentration of GEM reaching the brain extracellular fluid (BECF) following IN delivery, with the goal of delivering therapeutic concentrations of nucleoside drugs to the CNS. Experimental methods included IN administration of fluorescein isothiocyanate-dextran beads (FD4), GEM and PV, in-vitro GEM recovery, in-vivo brain microdialysis for BECF collection, HPLC analysis to measure GEM in BECF, histopathology, western blot analysis and immunofluorescence localization. Distribution studies with FD4 showed significant deposition in the ethmoid turbinates, suggesting drug uptake through olfactory epithelium. Clinically relevant doses of PV (up to 1.4% IN) did not cause histological evidence of cytotoxicity or inflammation in nasal epithelia, lung, liver, spleen, or kidney. Pharmacokinetics of GEM in BECF for PV (1.4%) + GEM (50mg/kg) treated animals showed almost four fold increase in area under the curve as compared to no PV treatment group. Western blot analysis suggested that IN PV treatment increased permeability through olfactory epithelial TJs by transiently decreasing the levels of TJ protein phospho- occludin. Immunofluorescence staining showed reversible alteration of occludin localization in olfactory epith (open full item for complete abstract)

Vitreoretinal diseases are currently being treated by intravitreal injection and controlled release implant. It is critical to know the drug distribution within the eye for adequate treatment of the diseases following these administrative methods. The vitreous diffusivity of drugs and vitreous outflow can play a significant role in drug distribution. Thus, the objective of this research is to: 1) compare the drug distribution for intravitreal injection and controlled release implant, 2) compare the drug distribution in the healthy eye with the pathophysiological eye having increased vitreous outflows, and 3) evaluate the coupled effects of vitreous outflows and diffusivities. A finite element method was applied to determine drug distribution by convective-diffusive transport processes using a 3D eye model. The implant having an equivalent amount of drug with intravitreal injection released drugs with a constant flux over a time period of 15 hrs. The implant reduced peak concentration about 40% and increased therapeutic time about 20% for the drug having 6×10-6 cm2/s of vitreous diffusivity, when compared with that of intravitreal injection for various vitreous outflows. As vitreous outflow increased from 0 to 1 µL/min, the drug half-life increased by 0.4 hrs for high vitreous diffusivity (1×10-5 cm2/s), whereas it decreased by 79.1 hrs for low vitreous diffusivity (1×10-7 cm2/s). Therefore, the implant can reduce the toxicity in vivo and result in a sustained release of the drug. Additionally, the convective-diffusive transfer and washout effect of drugs should be considered in the design of delivery strategies to treat vitreoretinal diseases. The present benchmark study allows for the prediction of drug distribution in the eye for the combined effects among drug delivery methods, diffusion of drug, and convection in the eye.

There continues to be a great demand for synthetic hosts that recognize targeted guests as efficiently as proteins recognize endogenous ligands. Artificial protein mimetics could act as chemical sensors, catalysts, or agents that transport drugs across cell membranes. We have created new protein mimetics with amino acid recognition elements that converge to a hydrophobic pocket in order to provide maximum binding free energy with a guest. The dynamic component of these host-[2]rotaxanes allows them to adjust to their environment, whether aqueous or non-aqueous, and does not detract significantly from the binding free energy. The host-[2]rotaxanes bind a variety of biomolecules like oligopeptides and some of them efficiently transport fluorescein and some fluoresceinated peptides into eukaryotic cells.

The intra-tumoral delivery of drugs is long-standing challenge in cancer chemotherapy because of complexity of the physiological barriers and biochemical mechanisms of tumor tissues. The transport of drugs or drug carriers from primary administration site to individual tumor cells involves multi-scale kinetic processes, including the distribution of drug from administration site to individual organs (whole body level), presentation of drug in tissues (organ level), and transport of drug in tumor interstitium (sub-organ level). The advancement of computation technology makes mathematical model of drug transport to be a novel strategy to optimize drug delivery and improve therapeutic efficiency. The goal of this dissertation is to develop multi-scale kinetic computational models to depict and predict drug transport in biological systems. A sub-organ level transport model was firstly developed to establish methodologies for predicting nanoparticles (NP) transport and disposition in tumor interstitium based on model parameters describing NP-cell interaction, as measured ex vivo (monolayer and spheroid cultures). Effects of several parameters (interstitial diffusivity, cell-surface binding and internalization) on the kinetics of NP transport after being extravasated from vessels were studied using the sub-organ level transport model. Secondly, we developed a multi-scale computational model by incorporating peritoneal and systemic pharmacokinetics (whole body level) into intra-tumoral transport model (organ and sub-organ lever) to investigate the effect of tumor size on paclitaxel transport and exposure in tumors after intraperitoneal (IP) administration. Model performance was verified by comparing the simulated results with the experimental data using paclitaxel in mice bearing peritoneal metastases of ovarian tumors. The pharmacodynamic effects of paclitaxel in tumors with different size were evaluated by comparing the model-predicted drug exposures at different tumor (open full item for complete abstract)

Nanomedicine has shown great promise for the treatment of a variety of complex diseases including cancer. The use of nanomaterials for non-covalent drug delivery has shown great success in the delivery of photodynamic therapy drugs in animal models, and has great potential as a general delivery vector for hydrophobic drugs. A detailed understanding of what physical forces dictate efficacy in the loading, transport, and delivery of non-covalent drugs is required for optimization and clinical translation. This thesis examines the non-covalent interactions between silicon phthalocyanine 4 (Pc 4) and polyethylene glycol coated gold nanoparticles (PEGylated Au NPs) through photophysics and transport studies. A detailed investigation of Pc 4's photophysical behavior in water both with and without Au NPs is presented, elucidating the role of intramolecular photoinduced electron transfer and aggregation behavior. Gel electrophoresis studies of PEGylated Au NPs described in this work provide insights on fundamental physical properties of NPs as well as the local environment through which they translate. This thesis provides a “bottom-up” approach to non-covalent drug delivery which will be helpful in translating non-covalent drug delivery to more complex systems.