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Antibody targeted liposomal systems

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dc.contributor.author Harasym, Troy O.
dc.date.accessioned 2009-04-01T19:35:24Z
dc.date.available 2009-04-01T19:35:24Z
dc.date.copyright 1997 en
dc.date.issued 2009-04-01T19:35:24Z
dc.identifier.uri http://hdl.handle.net/2429/6702
dc.description.abstract Despite success in the development of clinically useful liposomal anticancer drugs, the advancement of targeted formulations has been limited to only a handful of successful studies in animal models of cancer. This thesis suggests that a fundamental lack of understanding of the biological fate of protein-conjugated liposomes has led to the limited success of targeted carriers. Three critical areas of fundamental importance have been identified to better understand the limited success: i) optimizing the physical and chemical attributes of protein targeted liposomal carriers for in vivo applications; ii) evaluation of the biological fate of liposomal carriers; and iii) factors influencing the association of targeting ligands with liposomes. These basic studies identify a number of parameters that will effectively facilitate the development of therapeutically useful targeted liposomes. The initial focus of this investigation was concerned with the rapid aggregation of liposomes that occurs during protein coupling on the liposome surface. By adding polyethylene glycol (PEG)-lipid anchor conjugates onto a liposome, reductions in liposome aggregation were observed. This study demonstrated that incorporation of a 2000 M.W. hydrophilic PEG polymer anchored to a phospholipid in the liposomal membrane at a final concentration of 2 mol% resulted in optimal inhibition of aggregation with no significant inhibition of target site binding and optimal circulation lifetimes. Further investigations focused on passive tumor accumulation of doxorubicin containing liposomes. These studies were completed with the objectives of assessing whether liposomes that reach extravascular spaces within tumors are available for targeting. Finally, experiments focused on the method of coupling antibody to a liposome, either through primary amines or carbohydrates. Results concluded that the conjugation of antibody via carbohydrates resulted in extended circulation lifetimes compared with antibody-conjugated through primary amines. Additional characterization raised concerns as to the stability of the antibody on the liposome in vivo and suggested that the extended plasma levels observed with the carbohydrate conjugated antibodies was a result of antibody instability on the liposome. These studies, therefore, suggest that the method of conjugation of antibody is vital to the circulation lifetimes of antibody-conjugated liposomes and will most certainly be of major importance to the accumulation of liposomes to target sites. en
dc.format.extent 8775034 bytes
dc.format.mimetype application/pdf
dc.language.iso eng en
dc.relation.ispartof Retrospective Theses and Dissertations, 1919-2007 en
dc.relation.ispartofseries UBC Retrospective Theses Digitization Project [http://www.library.ubc.ca/archives/retro_theses/]
dc.title Antibody targeted liposomal systems en
dc.type Text
dc.degree.name Doctor of Philosophy - PhD en
dc.degree.discipline Biochemistry and Molecular Biology en
dc.degree.grantor University of British Columbia
dc.date.graduation 1997-11 en
dc.type.text Thesis/Dissertation
dc.description.affiliation Medicine, Faculty of en
dc.degree.campus UBCV en
dc.description.scholarlevel Graduate en

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