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UBC Theses and Dissertations
Biophysical and anticancer properties of mitoxantrone in programmable fusogenic vesicles Adlakha-Hutcheon, Gitanjali
Abstract
This thesis characterizes programmable fusogenic vesicles (PFVs) and examines their usefulness as carriers for an anticancer drug. PFVs are cationic liposomes designed to exhibit time-dependent destabilization. They consist of non-bilayer-forming lipids that are stabilized into a bilayer by exchangeable poly(ethylene glycol)-conjugated lipids (PEGlipids). The rate at which the vesicles destabilize is determined by the rate at which the bilayer stabilizing component, PEG-phosphatidylethanolamine (PEG-PE), exchanges out of the vesicle. In turn, this exchange rate is controlled by the acyl composition of the PEG-PE. PFVs are composed of l,2-dioleoyl-5«-glycero-3-phosphoethanolamine (DOPE), cholesterol (CHOL), ArN-dioleyl-N, Af-dimethylammonium chloride (DODAC) and a PEGconjugated lipid. The morphology of PFVs was examined as a function of lipid composition using cryo-transmission electron microscopy (cryo-TEM). While predominantly unilamellar, PFVs exhibit a variety of morphologies, including spherical, discoid and invaginated shapes. In the absence of PEG-lipid, PFVs formed in distilled water are spherical unilamellar structures but aggregation/fusion is observed when these systems are placed in isotonic saline. An essential finding is that despite the high proportion of non-bilayer-forming lipids in PFVs, these vesicles can efficiently accumulate the anticancer drug mitoxantrone in response to an imposed transmembrane proton gradient. Release of intravesicular contents of PFVs was demonstrated using radiolabeled sucrose. The rates of plasma elimination and biodistribution of PFVs and mitoxantrone-loaded PFVs were characterized as functions of PEG-PE acyl chain length. The presence of mitoxantrone did not alter the time-course of elimination of PFVs from the circulation. The rate of elimination of PFVs from the circulation depended on the chain length of PEG-lipid anchor. This is because long chain lengths of PEG-PE slow its loss from the PFV surface and, in turn, prolong the blood residence of PFVs. For instance, PFVs containing PEG-1,2-distearoyl-s«-phosphoethanolamine (DSPE) showed the slowest exchange and the longest blood residence times among the three anchors examined. The efficacy and accumulation within tumors of mitoxantrone-loaded PFVs were examined using a human colon carcinoma (LSI80) xenograft in severe combined immune deficient (SCID) mice. PFVs prepared with a slow-exchanging PEG-lipid delayed tumor progression more effectively than either PFVs that are rapidly eliminated from the circulation or conventional liposomes. Efficacy of mitoxantrone-loaded PFVs was also evaluated against a murine tumor model in which disease progression occurs primarily in the liver. All PFV formulations were significantly more active against this tumor model than free mitoxantrone or mitoxantrone-loaded conventional liposomes suggesting that PFVs are capable of releasing drug more efficiently than conventional formulations.
Item Metadata
Title |
Biophysical and anticancer properties of mitoxantrone in programmable fusogenic vesicles
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Creator | |
Publisher |
University of British Columbia
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Date Issued |
1999
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Description |
This thesis characterizes programmable fusogenic vesicles (PFVs) and examines their
usefulness as carriers for an anticancer drug. PFVs are cationic liposomes designed to
exhibit time-dependent destabilization. They consist of non-bilayer-forming lipids that are
stabilized into a bilayer by exchangeable poly(ethylene glycol)-conjugated lipids (PEGlipids).
The rate at which the vesicles destabilize is determined by the rate at which the
bilayer stabilizing component, PEG-phosphatidylethanolamine (PEG-PE), exchanges out of
the vesicle. In turn, this exchange rate is controlled by the acyl composition of the PEG-PE.
PFVs are composed of l,2-dioleoyl-5«-glycero-3-phosphoethanolamine (DOPE),
cholesterol (CHOL), ArN-dioleyl-N, Af-dimethylammonium chloride (DODAC) and a PEGconjugated
lipid. The morphology of PFVs was examined as a function of lipid composition
using cryo-transmission electron microscopy (cryo-TEM). While predominantly unilamellar,
PFVs exhibit a variety of morphologies, including spherical, discoid and invaginated shapes.
In the absence of PEG-lipid, PFVs formed in distilled water are spherical unilamellar
structures but aggregation/fusion is observed when these systems are placed in isotonic
saline. An essential finding is that despite the high proportion of non-bilayer-forming lipids
in PFVs, these vesicles can efficiently accumulate the anticancer drug mitoxantrone in
response to an imposed transmembrane proton gradient. Release of intravesicular contents of
PFVs was demonstrated using radiolabeled sucrose.
The rates of plasma elimination and biodistribution of PFVs and mitoxantrone-loaded
PFVs were characterized as functions of PEG-PE acyl chain length. The presence of
mitoxantrone did not alter the time-course of elimination of PFVs from the circulation. The
rate of elimination of PFVs from the circulation depended on the chain length of PEG-lipid anchor. This is because long chain lengths of PEG-PE slow its loss from the PFV surface and, in turn, prolong the blood residence of PFVs. For instance, PFVs containing PEG-1,2-distearoyl-s«-phosphoethanolamine (DSPE) showed the slowest exchange and the longest
blood residence times among the three anchors examined.
The efficacy and accumulation within tumors of mitoxantrone-loaded PFVs were
examined using a human colon carcinoma (LSI80) xenograft in severe combined immune
deficient (SCID) mice. PFVs prepared with a slow-exchanging PEG-lipid delayed tumor
progression more effectively than either PFVs that are rapidly eliminated from the circulation
or conventional liposomes. Efficacy of mitoxantrone-loaded PFVs was also evaluated
against a murine tumor model in which disease progression occurs primarily in the liver. All PFV formulations were significantly more active against this tumor model than free
mitoxantrone or mitoxantrone-loaded conventional liposomes suggesting that PFVs are
capable of releasing drug more efficiently than conventional formulations.
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Extent |
14886119 bytes
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Genre | |
Type | |
File Format |
application/pdf
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Language |
eng
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Date Available |
2009-07-02
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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 |
10.14288/1.0089255
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URI | |
Degree | |
Program | |
Affiliation | |
Degree Grantor |
University of British Columbia
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Graduation Date |
1999-11
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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.