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dc.contributor.advisorChong, Parkson Lee-Gau
dc.creatorDaswani, Varsha
dc.date.accessioned2020-11-03T16:23:44Z
dc.date.available2020-11-03T16:23:44Z
dc.date.issued2015
dc.identifier.other958157289
dc.identifier.urihttp://hdl.handle.net/20.500.12613/2754
dc.description.abstractCombretastatin A4 phosphate (CA4P) is a potent vascular disrupting agent utilized in the treatment of cancer. The observed rapid vascular shutdown post administration as well as its potency at 1/10th of the established maximum tolerated dose (MTD) have made it one of the most prevalent tubulin binding agents. CA4P is currently involved in 19 clinical trials. Unfortunately, as is the case with most forms of chemotherapy, the off target effects associated with its use can be prohibitive for a large percentage of cancer patients. The advantages associated with the liposomal encapsulation of chemotherapeutic agents have been established for over 20 years and are shown to decrease off target effects whilst increasing stability, bioavailability, and circulation time. Liposomes comprised of conventional phospholipids, such as 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC), are usually stabilized by the incorporation of cholesterol. However, the addition of cholesterol to liposomal formulations is concerning due to the capability of cholesterol to form oxysterol molecules and exacerbate other preexisting conditions such as hypertension or cardiovascular disease. With this study we aim to enhance the usage of CA4P through liposomal encapsulation in order to reduce some of the associated off target effects and increase bioavailability and overall efficacy. We also aimed to enhance the stability of our lipid vesicles through the incorporation of bipolar tetraether lipids isolated from the thermoacidophilic archaea S. acidocaldarius. The polar lipid fraction E (PLFE) lipids studied here have previously been shown to generate highly stable lipid vesicles. The liposomal formulation studied here included the encapsulation of the anti-cancer drug CA4P in PLFE liposomes. With this work we characterized our liposomes to optimize their drug loading, membrane stability, size, colloidal stability, and membrane surface charge. We also identified a photochemical isomerization reaction occurring in our CA4P samples and then proceeded to characterize the fluorescence and aggregation behavior of our CA4P isoforms. From our studies of CA4P in solution we observed a red shift in the excitation spectra of CA4P with increasing concentrations. This bathochromic shift is characteristic with the formation of j-aggregates. The CA4P concentrations with the most dramatic red shift corresponded exactly with the drug concentrations associated with self-quenching behavior. From these studies we determined the effects of increased CA4P concentration on fluorescence intensity, drug aggregation and how these phenomena can be utilized and exploited to maximize liposomal drug loading and decrease rate constants of drug leakage and cytotoxicity. The end goal of liposomal chemotherapeutic formulations is a stable, controlled release of as much encapsulated drug as possible. With the thorough understanding of our membrane system, drug fluorescence and CA4P aggregation behavior; we can maximize our encapsulated drug loading as well as create a stable liposomal formulation with a predictable CA4P release.
dc.format.extent131 pages
dc.language.isoeng
dc.publisherTemple University. Libraries
dc.relation.ispartofTheses and Dissertations
dc.rightsIN COPYRIGHT- This Rights Statement can be used for an Item that is in copyright. Using this statement implies that the organization making this Item available has determined that the Item is in copyright and either is the rights-holder, has obtained permission from the rights-holder(s) to make their Work(s) available, or makes the Item available under an exception or limitation to copyright (including Fair Use) that entitles it to make the Item available.
dc.rights.urihttp://rightsstatements.org/vocab/InC/1.0/
dc.subjectBiochemistry
dc.subjectBiophysics
dc.subjectChemistry
dc.subjectAggregation
dc.subjectCancer
dc.subjectDrug
dc.subjectFluorescence
dc.subjectLiposomes
dc.titleFluorescence and aggregation properties of the anti-cancer drug, CA4P, in archaeal liposomes
dc.typeText
dc.type.genreThesis/Dissertation
dc.contributor.committeememberSoprano, Dianne R.
dc.contributor.committeememberRothberg, Brad S.
dc.contributor.committeememberGamero, Ana
dc.contributor.committeememberRamirez, Servio H.
dc.description.departmentBiomedical Sciences
dc.relation.doihttp://dx.doi.org/10.34944/dspace/2736
dc.ada.noteFor Americans with Disabilities Act (ADA) accommodation, including help with reading this content, please contact scholarshare@temple.edu
dc.description.degreePh.D.
refterms.dateFOA2020-11-03T16:23:44Z


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