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UBC Theses and Dissertations
Antibody targeted liposomal systems Harasym, Troy O.
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.
Item Metadata
Title |
Antibody targeted liposomal systems
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Creator | |
Publisher |
University of British Columbia
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Date Issued |
1997
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Description |
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.
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Extent |
8775034 bytes
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Genre | |
Type | |
File Format |
application/pdf
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Language |
eng
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Date Available |
2009-04-01
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Provider |
Vancouver : University of British Columbia Library
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Rights |
For non-commercial purposes only, such as research, private study and education. Additional conditions apply, see Terms of Use https://open.library.ubc.ca/terms_of_use.
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DOI |
10.14288/1.0099209
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URI | |
Degree | |
Program | |
Affiliation | |
Degree Grantor |
University of British Columbia
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Graduation Date |
1997-11
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Campus | |
Scholarly Level |
Graduate
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Aggregated Source Repository |
DSpace
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Item Media
Item Citations and Data
Rights
For non-commercial purposes only, such as research, private study and education. Additional conditions apply, see Terms of Use https://open.library.ubc.ca/terms_of_use.