Efforts to enhance the utility of photodynamic therapy as a non-invasive method for treating certain cancers have often involved the design of dye sensitizers with increased singlet oxygen efficiency. More recently, however, sensitizers with greater selectivity for tumor cells than surrounding tissue have been targeted. The present study provides an approach to the modification of the known photosensitizer zinc phthalocyanine (ZnPc), to enhance its solubility and delivery to cancer cells. Targeting a photosensitizer to the site of action improves the efficacy of the sensitizer in photodynamic therapy. In this work we used PLGA-b-PEG to encapsulate a new zinc phthalocyanine derivative, 2(3), 9(10), 16(17), 23(24)-tetrakis-(4'-methyl-benzyloxy) phthalocyanine zinc(II) (ZnPcBCH3), to enhance uptake into A549 cells, a human lung cancer cell line. ZnPcBCH3 exhibited the same photochemical properties as the parent compound ZnPc but gave increased solubility in organic solvents, which allowed for efficient encapsulation. In addition, the encapsulated dye showed a near 500-fold increase in phototoxicity for A549 cancer cells compared to free dye.

We have identified a small library of novel substituted 9-aminoacridine derivatives that inhibit cell proliferation of pancreatic cancer cell lines by inducing apoptosis [Goodell, J.R. et al., 2008. J. Med. Chem. 51, 179-182.]. To further investigate their antiproliferative activities, we have assessed the antiproliferative activity of these acridine-based compounds against several pancreatic cancer cell lines. All four compounds used in this study inhibited the proliferation of pancreatic cancer cell lines in vitro. In addition, we have employed a xenograft tumor model and found that these compounds also inhibit the proliferation of pancreatic cancer in vivo. In light of the potential importance of the anticancer activity of these acridine-based compounds, we have conducted a series of biochemical assays to determine the effect of these compounds on human topoisomerase II. Unlike amsacrine, these compounds do not poison topoisomerase II. Similar to amsacrine, however, these compounds intercalate into DNA in a way that they would alter the apparent topology of the DNA substrate. Thus, inhibition of the relaxation activity of topoisomerase II by these compounds has been reexamined using a DNA strand passage assay. We have found that these compounds, indeed, inhibit the catalytic activity of topoisomerase II. Thus, these novel acridine-based compounds with anti-pancreatic cancer activity are catalytic inhibitors, not poisons, of human topoisomerase II.

α,α′-Bis[3-(N,N-diethylcarbamoyl)piperidino]-p-xylene enhances human blood platelet membrane integrity by exerting a stabilizing action at the level of the dense tubular system in surface membrane complexes known to sequester platelet calcium.

Several passive energy dissipation devices have been implemented in practice as the seismic protective systems to mitigate structural damage caused by earthquakes. The solid viscoelastic dampers are among such passive energy dissipation systems. To examine the response reducing effectiveness of these dampers, it is necessary that engineers are able to conduct response analysis of structures installed with added dampers accurately and efficiently. The main objective of this work, therefore, is to develop formulations that can be effectively used with various models of the viscoelastic dampers to calculate the seismic response of a structure-damper system. To incorporate the mechanical effect from VE dampers in the structural dynamic design, it is important to use a proper force-deformation model to correctly describe the frequency dependence of the damper. The fractional derivative model and the general linear model are capable of capturing the frequency dependence of viscoelastic materials accurately. In our research, therefore, we have focused on the development of systematic procedures for calculating the seismic response for these models. For the fractional derivative model, we use the G1 and L1 algorithms to derive various numerical schemes for solving the fractional differential equations for earthquake motions described by acceleration time histories at discrete time points. For linear systems, we also develop a modal superposition method for this model of the damper. This superposition approach can be implemented to obtain the response time history for seismic input defined by the ground acceleration time history. For random ground motion that is described stochastically by the spectral density function, we derive an expression based on random vibration analysis to compute the mean square response of the system. It is noted that the numerical computations involved with the fractional derivative model can be complicated and cumbersome. To alleviate computation difficulty, we explore the use of a general linear model with Kelvin chain analog as a physical representation of the damper properties. The parameters in the model are determined through a curve fitting optimization process. To simplify the analytical work, a self-adjoint system of state equations are formulated by introducing auxiliary displacements for the internal elements in the Kelvin chain. This self-adjoint system can then be solved by using the modal superposition method, which can be extended to develop a response spectrum approach to calculate the seismic design response for the structural system for seismic inputs defined by design ground response spectra. Numerical studies are carried out to demonstrate the applicability of these formulations. Results show that all the proposed approaches provide accurate response values, and the response reduction effects of the viscoelastic dampers can be evaluated to assess their performance using these models and methods. However, the use of a general linear model of the damper is the most efficient. It can capture frequency dependence of the storage and loss moduli as well as the fractional derivative model. The calculation of the response by direct numerical integration of the equations of motion or through the use of the modal superposition approach is significantly simplified, and response spectrum formulation for the calculation of seismic response of design interest can be conveniently formulated. / Ph. D.

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Two major aspects of CCK-induced satiety were examined in the food deprived sham-feeding rat: the kinetics of the inhibition of feeding produced by CCK and the interaction of CCK-induced satiety with oropharyngeal stimulation. Four results were presented regarding the kinetics of the CCK satiety effect. First, CCk administered coincident with the initiation of sham feeding inhibits feeding in a dose-related manner. Second, the increased efficacy of the higher dose of CCK delivered at the same time as sham feeding results from an increase in the size of maximum suppression and an increase in the time of suppression effected via a decreased latency to suppression. Third, CCk delivered 15 minutes before sham feeding begins has no effect on feeding. Fourth, the administration of a long-lasting derivative of CCK 15 minutes prior to the initiation of sham feeding can suppress intake. Two results were presented regarding the role of oropharyngeal stimulation in CCK-induced satiety. First, it was shown that oropharyngeal stimulation enhances the satiety action of CCK. Second, the amount and pattern of feeding inhibition produced by CCK are equivalent regardless of whether the peptide is administered coincident with, or some time after, the initiation of sham feeding. The implications of these results for the therapeutic use of this peptide and its role in producing satiety are discussed. / Thesis / Master of Arts (MA)