- Library Home /
- Search Collections /
- Open Collections /
- Browse Collections /
- UBC Theses and Dissertations /
- Role of liposome mediated drug delivery and drug release...
Open Collections
UBC Theses and Dissertations
UBC Theses and Dissertations
Role of liposome mediated drug delivery and drug release in determining the therapeutic activity of liposomal formulations of mitoxantrone Lim, Howard J.
Abstract
Although liposomal accumulation at the target site is an important issue, the critical parameter defining the activity of a liposomal formulation is drug release, a factor that includes where, when, and how fast the therapeutic agent dissociates from the liposomal carrier. This point was investigated using two liposomal formulations of the anti-cancer drug mitoxantrone. Mitoxantrone was encapsulated via a pH gradient method in liposomes prepared of 1,2 distearoyl-sn-glycero-3-phosphocholine (DSPC)/cholesterol (Choi) (55:45 mol ratio) or 1,2 dimyristoyl-sn-glycero-3-phosphocholine (DMPC)/Chol (55:45 mol ratio), the latter exhibiting a greater rate of drug release in vivo. Using a model of liver localized cancer consisting of BDF1 mice inoculated with either P388 or L1210 cells intravenously (/.v.), it was demonstrated that a single dose of DMPC/Chol mitoxantrone (10 mg/kg) administered i.v. resulted in 100% 60 day survival. In contrast, no long-term survivors were obtained in animals treated with free or DSPC/Chol mitoxantrone. Drug levels in the liver were determined and demonstrate that greatest drug delivery was achieved with the DSPC/Chol liposomal formulation. In an effort to address whether liposome mediated delivery or drug release is the dominant factor determining therapeutic activity, additional experiments examined the role of drug release at tumour sites where liposome accumulation is slow. As demonstrated in subcutaneous LSI80 and A431 tumours grown on the backs of SCID/RAG-2 mice, the DMPC/Chol formulation demonstrated greater activity in the LSI80 tumour model and was as efficacious as the DSPC/Chol formulation when treating A431 tumours. These data emphasize the importance of designing liposomal formulations that optimize drug biological availability rather than drug delivery. In an effort to understand factors that are important in governing the activity of DMPC/Chol liposomal mitoxantrone used to treat liver localized disease, studies modulating liposomal accumulation in the liver were completed. Two methods were used to effect reductions in liposome delivery to the liver: the use of PEG-modified lipids and hepatic mononuclear phagocyte system (MPS) blockade. Both methods reduced liposomal drug accumulation in the liver by a factor of 2 to 3 fold. A significant reduction in therapeutic activity was observed when PEG-modified lipids were incorporated into the DMPC/Chol mitoxantrone formulation; however, M P S blockade did not affect anti-tumour activity. Long term survival (>60 days) was still observed in animals where hepatic MPS blockade effected elimination o f liver Kupffer cells. It is concluded that reductions in therapy observed for the PEG-modified DMPC/Chol mitoxantrone are likely due to inhibition of cell binding and processing. Conversely it is suggested that the activity of the DMPC/Chol mitoxantrone is dependent on cell processing, but the Kupffer cells do not play a significant role in this processing event.
Item Metadata
Title |
Role of liposome mediated drug delivery and drug release in determining the therapeutic activity of liposomal formulations of mitoxantrone
|
Creator | |
Publisher |
University of British Columbia
|
Date Issued |
1999
|
Description |
Although liposomal accumulation at the target site is an important issue, the critical parameter
defining the activity of a liposomal formulation is drug release, a factor that includes where,
when, and how fast the therapeutic agent dissociates from the liposomal carrier. This point was
investigated using two liposomal formulations of the anti-cancer drug mitoxantrone.
Mitoxantrone was encapsulated via a pH gradient method in liposomes prepared of 1,2
distearoyl-sn-glycero-3-phosphocholine (DSPC)/cholesterol (Choi) (55:45 mol ratio) or 1,2
dimyristoyl-sn-glycero-3-phosphocholine (DMPC)/Chol (55:45 mol ratio), the latter exhibiting a
greater rate of drug release in vivo. Using a model of liver localized cancer consisting of BDF1
mice inoculated with either P388 or L1210 cells intravenously (/.v.), it was demonstrated that a
single dose of DMPC/Chol mitoxantrone (10 mg/kg) administered i.v. resulted in 100% 60 day
survival. In contrast, no long-term survivors were obtained in animals treated with free or
DSPC/Chol mitoxantrone. Drug levels in the liver were determined and demonstrate that
greatest drug delivery was achieved with the DSPC/Chol liposomal formulation. In an effort to
address whether liposome mediated delivery or drug release is the dominant factor determining
therapeutic activity, additional experiments examined the role of drug release at tumour sites
where liposome accumulation is slow. As demonstrated in subcutaneous LSI80 and A431
tumours grown on the backs of SCID/RAG-2 mice, the DMPC/Chol formulation demonstrated
greater activity in the LSI80 tumour model and was as efficacious as the DSPC/Chol formulation
when treating A431 tumours. These data emphasize the importance of designing liposomal
formulations that optimize drug biological availability rather than drug delivery.
In an effort to understand factors that are important in governing the activity of DMPC/Chol
liposomal mitoxantrone used to treat liver localized disease, studies modulating liposomal
accumulation in the liver were completed. Two methods were used to effect reductions in
liposome delivery to the liver: the use of PEG-modified lipids and hepatic mononuclear
phagocyte system (MPS) blockade. Both methods reduced liposomal drug accumulation in the
liver by a factor of 2 to 3 fold. A significant reduction in therapeutic activity was observed when
PEG-modified lipids were incorporated into the DMPC/Chol mitoxantrone formulation;
however, M P S blockade did not affect anti-tumour activity. Long term survival (>60 days) was
still observed in animals where hepatic MPS blockade effected elimination o f liver Kupffer cells.
It is concluded that reductions in therapy observed for the PEG-modified DMPC/Chol
mitoxantrone are likely due to inhibition of cell binding and processing. Conversely it is
suggested that the activity of the DMPC/Chol mitoxantrone is dependent on cell processing, but
the Kupffer cells do not play a significant role in this processing event.
|
Extent |
10706178 bytes
|
Genre | |
Type | |
File Format |
application/pdf
|
Language |
eng
|
Date Available |
2009-07-02
|
Provider |
Vancouver : University of British Columbia Library
|
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.
|
DOI |
10.14288/1.0089294
|
URI | |
Degree | |
Program | |
Affiliation | |
Degree Grantor |
University of British Columbia
|
Graduation Date |
1999-11
|
Campus | |
Scholarly Level |
Graduate
|
Aggregated Source Repository |
DSpace
|
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.