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"In vitro" and "in vivo" drug targeting using biotinylated immunoliposomes

Schnyder, Anita. "In vitro" and "in vivo" drug targeting using biotinylated immunoliposomes. 2005, PhD Thesis, University of Basel, Faculty of Science.

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Official URL: http://edoc.unibas.ch/diss/DissB_7498

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Abstract

The aim of my thesis was the optimization, characterization and application of a new, innovative drug carrier system which can be used to target pharmaceuticals to diseased tissues and organs. In the present study, a non-covalent biotin-streptavidin coupling procedure for the preparation of pegylated immunoliposomes is presented which simplifies the attachment of targeting vectors to sterically stabilized liposomes. The OX26 monoclonal antibody against the rat transferrin receptor was used as a targeting vector.
Immunostaining experiments with the OX26 monoclonal antibody followed by fluorescent confocal microscopy revealed immunofluorescence labeling of the transferrin receptor on muscle and on glioma cells. Uptake experiments with these cells demonstrated cellular uptake and accumulation of small molecules (daunomycin, fluorescent probes) or macromolecules such as fluorescent oligonucleotides, within an intracellular compartment.
Cellular uptake of liposomal daunomycin by multidrug-resistant cells was dose- and time-dependent and was associated with a clear pharmacological (i.e. cytotoxic) effect. Cytotoxic effects of liposomal formulations of daunomycin, in contrast to the free drug, were apparent only after prolonged incubation periods being indicative of a slow intracellular unpacking and release of liposomal daunomycin. With respect to expression plasmids (i.e. gene targeting), only marginal levels of gene expression were observed in vitro.
Pharmacokinetics and tissue distribution studies in the rat revealed a substantially increased plasma half-live of liposomal drug compared to free drug. Brain accumulation of daunomycin in OX26-immunoliposomes occurred in higher levels as compared to brain uptake of free daunomycin or daunomycin incorporated within pegylated liposomes or unspecific IgG2a isotype control immunoliposomes. Such OX26-mediated effects were not observed in other tissues such as spleen, liver, muscle or kidney.
Our experiments indicate that immunoliposomes can be used to target small drug molecules as well as macromolecules, such as oligonucleotides and expression plasmids, to cells and tissues.
These findings demonstrate that immunoliposomes are a versatile and promising tool for future drug development in regard to both, galenic and therapeutical research. For clinical administrations, a better understanding of cellular uptake and release mechanisms are needed.
Advisors:Huwyler, Jörg
Committee Members:Krähenbühl, Stephan and Drewe, Jürgen
Faculties and Departments:05 Faculty of Science > Departement Pharmazeutische Wissenschaften > Pharmazie > Pharmazeutische Technologie (Huwyler)
Item Type:Thesis
Thesis no:7498
Bibsysno:Link to catalogue
Number of Pages:142
Language:German
Identification Number:
Last Modified:30 Jun 2016 10:41
Deposited On:13 Feb 2009 15:35

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