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One of earlier challenges in treating cancer was utilizing drugs that are powerful yet do not cause severe toxicity to patients. Although the use of liposomal drugs has somewhat met that challenge, our objective now is to create liposomal drugs with an even better drug efficacy and further reduced toxicity. Doxorubicin hydrochloride (DXO), for example, is an anticancer drug used to treat many types of cancers, but it is toxic to the gastrointestinal tract and the heart. Encapsulating DXO into liposomes as done in the first FDA-approved liposomal DXO, Doxil, minimizes toxicity and improves the half-life, allowing more opportunities for the drug to reach the tumor. While liposomal DXO is in the market with an annual sale of approximately 450 million dollars, the addition of cholesterol and lipids with polyethylene glycol (PEG) in the formulation increase liposome stability and circulation time, but can give rise to other concerns such as potential harm to the patient and reduction in drug loading/release. In addition, in hopes of increasing drug accumulation at the diseased tissue, the use of active or targeted nanoparticles has been explored for selective drug delivery. However, despite ongoing efforts to design and test targeted nanocarriers for drug delivery, there is no known targeted liposome commercially available at this time. This illustrates that there is still room to improve the formulation of the liposomal carriers in the areas of stability, specificity to the cancer sites, and maximum drug at diseased sites. The main focus of our research is to develop novel liposomal carriers that have a higher therapeutic index and lower cytotoxicity than currently used liposomal drugs. In this research, we were able to construct two stable liposomal systems. First, we constructed a liposomal system having the ability to specifically target phosphatidylserine (PS) exposed tissues. This liposomal system contains 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) and hydrophobic PS-targeting molecule bis-dipicolylamine-Zn-Cy3[C22,22] (abbreviated DPA-Cy3[22,22]). We have tested stability and PS binding ability of DPA-Cy3[22,22]/POPC liposomal carriers using light scattering and ion-exchange chromatography, respectively. In addition, with confocal microscopy and flow cytometry, we have tested DPA-Cy3[22,22]/POPC liposomes’ affinity to cancer cells. Furthermore, cell viability assay was used to determine the cytotoxic effect of DPA-Cy3[22,22]/POPC liposomes on cancer cells and non-cancer cells. In short, we found that DPA-Cy3[22,22]/POPC liposomes were stable, displayed binding to PS-exposed cells, and were taken up by PS-exposed cells inducing considerable cytoxicity. Second, we have developed and characterized the physical properties of thermosensitive liposomes made of archaeal bipolar tetraether lipids (BTL) and “conventional” monopolar diester lipids. These liposomes are also termed hybrid archaeosomes. Specifically, we used the polar lipid fraction E (PLFE) isolated from the thermoacidophilic archaeon Sulfolobus acidocaldarius as the BTL component of the hybrid archaeosomes. Dynamic light scattering and zeta potential measurements showed that the presence of PLFE greatly stabilizes liposomes. The most striking result is that at 25-30 mol% PLFE in DPPC liposomes, there is a dramatic change in zeta potential with temperature. The most abrupt change was detected in 30 mol% PLFE in DPPC, where the zeta potential changes from ~45mV at 37˚C to ~5mV at 42˚C. This drastic change in liposome zeta potential by temperature is unprecedented and could be used to develop new thermosensitive liposomes. This dramatic change in zeta potential is likely to result from gross changes in membrane structure by temperature at particular PLFE mole fractions. To further characterize PLFE/DPPC hybrid archaeosomes, we have used steady state nano-second fluorometry. The fluorescent data show that from 37˚C to 43˚C, the probe diphenylhexatrine (DPH) in the PLFE/DPPC mixtures experience a decrease in order parameter and an increase in rotational motion. With entrapped DXO we found that below 37˚C, the drug release from hybrid archaeosomes is slow. However, when the temperature was raised to above 39˚C, the initial drug release rate constant was increased by a factor of 2. Taken together, the findings suggest that a mild temperature jump changes the membrane packing and dynamics of the PLFE/DPPC mixture, making the membrane more permeable for small molecules. Additionally, confocal fluorescence microscopy showed that these hybrid archaeosomes can be taken up by live cells (e.g., MCF-7 breast cancer cells) and deliver entrapped drug molecules to the cell’s nucleus, with a rate significantly lower than that obtained from conventional diester liposomes. Our results indicate that both of these two novel liposomal systems have great potential to be used for delivery of therapeutic agents such as small drug molecules (e.g., DXO), siRNA, DNA, or peptides/proteins for cancer treatment and various other purposes. Unlike currently available liposomal drugs, DPA-Cy3[22,22] containing liposomes could be useful for targeting PS-exposed diseased tissues. 30 mol% PLFE/DPPC archeosomes are a unique thermosensitive liposome system with extraordinary stability at the body temperature and able to release entrapped drugs molecules when the local temperature of the diseased tissue is subject to hyperthermic treatment. / Biochemistry

The annual incidence of abdominal aortic aneurysm (AAA) is approximately 0.4% to 0.67% in Western populations on average. Without timely surgical treatment, AAA can progress to life-threatening rupture with mortality rates as high as 80%, which ranks the 15th leading cause of death in the United States. AAA development is progressively increasing with renal dysfunction. Chronic kidney disease (CKD), an independent risk factor for AAA, is a progressive disease that affects >10% of the general population worldwide. In the United States, 2023, the Centers for Disease Control and Prevention reported that 14% of US adults are estimated to have CKD. Among 153 uremic toxins which are accumulated in plasma of CKD patients, Trimethylamine N-oxide (TMAO) has recently emerged as a gut microbiota-generated uremic toxin and the plasma TMAO levels are significantly elevated in patients with CKD and AAA. However, the role of TMAO in promoting endothelial cell activation, vascular inflammation and progression of AAA remains unclear. The non-canonical inflammasome activation has been described as a pathway that is dependent on caspase-4 (human) and caspase-11 (mice) in response cytosolic Lipopolysaccharide (LPS) stimulation. The activated caspase-4/11 will trigger the cleavage of Gasdermin D (GSDMD) and the formation of N-terminal GSDMD cell membrane pore. Then, the proinflammatory cytokines such as IL-1b will be released. However, the role of caspase-11 pathway in abdominal aortic aneurysm remains unknown. We hypothesize that TMAO promotes endothelial cell activation, vascular inflammation, and progression of AAA via caspase-11 pathway; the deficiency of caspase-11 will inhibit the development of AAA. In this project, we demonstrated the role of TMAO in promoting endothelial cell activation, vascular inflammation and accelerating the progression of abdominal aortic aneurysm. We performed histological study to demonstrate that the vascular structure was damaged including increased elastin breaks and non-uniform collagen deposition in TMAO promoted Angiotensin II (Ang II)-induced AAA in Apolipoprotein E (ApoE) KO background. In addition, we performed myograph for determine endothelial vascular dysfunction and found that the endothelial-dependent vessel relaxation to acetylcholine (ACh) was damaged by TMAO stimulation, but endothelial-independent vessel relaxation to Sodium nitroprusside (SNP) was not affected by Ang II+TMAO. For mechanism study, we found that the TMAO receptor eukaryotic translation initiation factor 2 alpha kinase 3 (EIF2AK3, also known as PERK) pathway activation, increased cytosolic LPS, increased activation of caspase-11 and increased proinflammatory cytokine release in aorta of Ang II-TMAO-induced AAA. Finally, we found that caspase-11 was required for Ang II-TMAO-induced trained immunity (also known as innate immune memory) and the progression of Ang II-TMAO-induced AAA was significantly inhibited in caspase-11/ApoE double knockout (DKO) mice compared to ApoE KO mice. Caspase-11 can be identified as a potential therapeutic target for inhibiting trained immunity and progression of AAA. / Biomedical Sciences

The non-random covalent binding to DNA by the intercalators 8-azido-ethidium, 7-azido-actinomycin D, anti-(+)-benzo (a) pyrene 7,8-diol 9,10-epoxide, and anti-($-$)-benzo (a) pyrene 7,8-diol 9,10-epoxide was investigated using techniques analogous to DNA sequencing. A computer-assisted methodology was subsequently developed that allowed the characterization of all sequence preferences of covalent binding up to the quartet level. All intercalators exhibited some preferences in binding. 7-azido-actinomycin D was most sequence selective and 8-azido-ethidium was least sequence selective. Next-nearest neighboring bases exert a major influence on the reactivities of the intercalators. The magnitude of the next-nearest neighbor influence is almost as great as the nearest-neighbor influence. There were certain sequence preferences of covalent binding shared by all intercalators. The sequence preference analysis indicated that 7-azido-actinomycin D and 8-azido-ethidium were excellent probes for evaluating the reversible binding of the parent actinomycin D and ethidium molecules. There were some differences in the sequence preferences of covalent binding by the two benzo (a) pyrene diol epoxide enantiomers. The potent carcinogenicity of the anti-(+)-isomer may be caused by the adduct at the exocyclic amine of guanine bases, since this isomer forms more of these adducts than the anti-($-$)-isomer. / Source: Dissertation Abstracts International, Volume: 51-07, Section: B, page: 3284. / Major Professor: Randolph L. Rill. / Thesis (Ph.D.)--The Florida State University, 1990.

Thesis (Ph.D.)--University of Illinois at Urbana-Champaign, 2008. / Source: Dissertation Abstracts International, Volume: 69-11, Section: B, page: 6638. Adviser: Yi Lu. Includes bibliographical references. Available on microfilm from Pro Quest Information and Learning.

Thesis (Ph.D.)--University of Illinois at Urbana-Champaign, 2006. / Source: Dissertation Abstracts International, Volume: 67-07, Section: B, page: 3643. Adviser: Robert B. Gennis. Includes bibliographical references (leaves 103-109) Available on microfilm from Pro Quest Information and Learning.

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There are many conflicting views about the blood-response to polymeric materials. In order to be satisfied that a material performs appropriately when used as a device in contact with blood it must be evaluated under relevant conditions. Central venous catheters suffer from problems related to thrombosis and embolism since they are implanted for very long periods of time within the vascular system. The aim of this study was to evaluate the most appropriate method for assessing catheter thrombogenicity, establish data for a number of relevant parameters and correlate these findings with various physico-chemica1 characteristics of the materials. Accordingly, a dynamic model was developed which allowed the assessment of platelet adhesion by measurement of "Cr-labelled platelets and platelet a-granule and lysosomal secretion by flow cytometry, after labelling with anti- GMPl40 and anti-GPS3 antibodies, in whole blood after the perfusion of the blood along the tubing at physiologically relevant shear rates (up to 1000 s") at 37OC. In addition, contact phase activation was assessed by measuring the time taken for an aliquot of plateletfree plasma to clot after contact with catheter material (partial thromboplastin time or P'IT) and the ability of the materials to cause factor XII activation by measuring the quantity of FXIIa-Cl-Inh complexes formed by enzyme-linked immunosorbent assay after the contact of platelet-free plasma with catheter tubing. An attempt was made at finding the identity of the proteins adsorbed onto silicone using a number of electrophoretic techniques. The ability of the materials to cause haemolysis and the cytotoxicity of an extract derived from the materials after SO days incubation in PBS including the identification of these potential leachables by supercritical fluid extraction was also investigated. In addition, these data were discussed in relation to parameters of surface roughness, as viewed by SEM and the ratio of hard and soft segments appearing at the material surface by XPS. It was found that significant differences could be detected in (i) platelet adhesion, where Pellethane was shown to have poor performance; (ii) a-granule release, where all the polyurethanes displayed better performance than any of the other materials and (iii) lysosomal granule release where most materials fared similarly, except for glass which was much worse. Silicone was shown to be best in the PIT assay, Pellethane worst. Surprisingly, no correlation was found with these results and those from FXIIa assay, where Desmopan and Davathane were highly active. New and important data on the initial activation kinetics and the ability of materials to activate factor XII are shown. Silicone produced the greatest haemolysis, PVC the greatest extract toxicity. No correlation was found between the physico-cbemical data and any of the biocompatibility data.