Stabilized antisense-lipid particles with enhanced intracellular delivery properties
department or school: Medicine, Faculty of
department or school: Biochemistry and Molecular Biology, Department of
data provider: DSpace
degree campus: UBCV
creator: Louie, Lenore Jennifer
issued: 2009-07-13T18:32:09Z
issued: 2000
related degree: Master of Science - MSc
degree grantor: University of British Columbia
description: Effective systemic delivery systems for DNA and RNA are essential to the successful clinical application of genetic drugs. Liposomal formulations of genetic drugs, such as antisense oligonucleotides (AS-ODN) and plasmid DNA, are difficult to achieve as the large size and highly charged nature of these molecules mitigates against the formation of small, neutral, serum stable carriers, which are required to achieve the long circulation times necessary for efficient delivery to disease sites such as tumors. Stabilized antisense-lipid particles (SALPs) are liposomal carriers of antisense oligonucleotides that exhibit high antisense-to-lipid ratios, long circulation lifetimes and accumulate preferentially at disease sites. As a result of high encapsulation efficiencies, SALPs are able to deliver large quantities of AS-ODN to target tissues. However, SALPs are relatively ineffective at delivering antisense molecules inside target cells. For AS-ODN to be effective in inhibiting gene expression, they must be internalized by the target cell, effectively released from endosomal compartments and translocated to the nucleus, their primary site of action. The studies conducted in this thesis examined methods to enhance the intracellular delivery of antisense oligonucleotides contained within SALP systems. In particular, we examined the effect of a surface associated cationic PEG-lipid (CPL4) on increasing cellular uptake of SALPs. Subsequent studies investigated the ability of dioleoylphosphatidylethanolamine (DOPE) in SALP systems to enhance nuclear delivery of AS-ODN sequences by promoting endosome destabilization. It is shown that the incorporation of CPL4 into distearylphosphatidylcholine/ cholesterol/ l,2-dioleoyl-3-[N,N-dimethylamino]propane/ PEG-CeramideC₁₄ (20/45/25/10 mol%) SALP was successful in increasing the cellular internalization of these vesicles but did not result in increased nuclear delivery of AS-ODN. Nuclear accumulation of oligonucleotides was achieved thro…
aggregated CHO: https://circle.library.ubc.ca/rest/handle/2429/10688
extent: 4358736 bytes
format: application/pdf
note: STABILIZED ANTISENSE-LIPID PARTICLES WITH ENHANCED INTRACELLULAR DELIVERY PROPERTIES by LENORE JENNIFER LOUIE B.Sc, The University of British Columbia, 1997 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER-OF SCIENCE in THE FACULTY OF GRADUATE STUDIES Department of Biochemistry and Molecular Biology We accept this thesis as conforming to the required standard THE UNIVERSITY OF BRITISH COLUMBIA June 2000 © Lenore Jennifer Louie, 2000 UBC Special Collections - Thesis Authorisation Form Page 1 of 1 In p r e s e n t i n g t h i s t h e s i s i n p a r t i a l f u l f i l m e n t of the requirements f o r an advanced degree at the U n i v e r s i t y of B r i t i s h Columbia, I agree that the L i b r a r y s h a l l make i t f r e e l y a v a i l a b l e f o r reference and study. I f u r t h e r agree that permission f o r extensive copying of t h i s t h e s i s f o r s c h o l a r l y purposes may be granted by the head of my department or by h i s or her r e p r e s e n t a t i v e s . I t i s understood that copying or p u b l i c a t i o n of t h i s t h e s i s f o r f i n a n c i a l gain s h a l l not be allowed without my w r i t t e n permission. The U n i v e r s i t y of B r i t i s h Columbia Vancouver, Canada http://www.library.ubc.ca/spcoll/thesauth.html 6/15/00 A B S T R A C T Effective systemic delivery systems for DNA and RNA are essential to the successful clinical application of genetic drugs. Liposomal formulations of genetic drugs, such as antisense oligonucleotides (AS-ODN) and plasmid DNA, are difficult to achieve as the large size and highly charged nature of these molecules mitigates against the formation of small, neutral, serum stable carriers, which are required to achieve the long circulation times necessary for efficient delivery to disease sites such as tumors. Stabilized antisense-lipid particles (SALPs) are liposomal carriers of antisense oligonucleotides that exhibit high antisense-to-lipid ratios…
has type: Thesis/Dissertation
date issued: 2000-11
is shown at: 10.14288/1.0089567
language: eng
degree discipline: Biochemistry and Molecular Biology
provider: Vancouver : University of British Columbia Library
publisher: University of British Columbia
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.
scholar level: Graduate
type: Text
identifier URI: http://hdl.handle.net/2429/10688