Peptide-Liposome Model Systems for Triggered Release PDF Download

Author: Camilla Skyttner
Publisher: Linköping University Electronic Press
ISBN: 9176853373
Category :
Languages : en
Pages : 94

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Book Description
Liposomes are widely used in drug delivery to improve drug efficacy and to reduce side effects. For liposome-encapsulated drugs to become bioavailable and provide a therapeutic effect they must be released, which typically is a slow process that primarily relies on passive diffusion, liposome rupture or endocytotic uptake. Achieving drug concentrations within the therapeutic window can thus be challenging, resulting in poor efficacy and higher risks drug resistance. Finding means to modulate lipid membrane integrity and to trigger rapid and efficient release of liposomal cargo is thus critical to improve current and future liposomal drug delivery systems. The possibilities to tailor lipid composition and surface functionalization is vital for drug delivery applications but also make liposomes attractive model systems for studies of membrane active biomolecules. The overall aim of this thesis work has been to develop new strategies for triggering and controlling changes in lipid membrane integrity and to study the interactions of membrane active peptides with model lipid membranes using both de novo designed and biologically derived synthetic amphipathic cationic peptides. Two different sets of designed peptides have been explored that can fold and heterodimerize into a coiled coil and helix-loop-helix fourhelix bundle, respectively. Conjugation of the cationic lysine rich peptides to liposomes triggered a rapid and concentration dependent release. The additions of their corresponding glutamic acid-rich complementary peptides inhibited the release of liposomal cargo. Possibilities to reduce the inhibitory effect by both proteolytic digestion of the inhibitory peptide and by means of heterodimer exchange have been investigated. Moreover, the effects of peptide size and composition and ability to fold have been studied in order to elucidate the factors that influence the membrane permeabilizing effects of the peptides. In addition, the membrane activity of a the two-peptide bacteriocin PLNC8? and PLNC8? has been explored using liposomes as a model system. PLNC8?? are expressed by Lactobacillus plantarum and were shown to display pronounced membrane-partition folding coupling, leading to rapid release of liposome encapsulated carboxyfluorescein. PLNC8?? also kill and suppressed growth of the gram-negative bacteria Porphyromonas gingivalis by efficiently damaging the bacterial membrane. Although membrane active peptides are highly efficient in perturbing lipid membrane integrity, possibilities to trigger release using external stimuli are also of large interest for therapeutic applications. Light-induced heating of liposome encapsulated gold nanoparticles (AuNPs) has been shown by others as a potential strategy to trigger drug release. To facilitate fabrication of thermoplasmonic liposome systems we developed a simple method for synthesis of small AuNPs inside liposomes, using the liposomes as nanoscale reaction vessels. The work presented in this thesis provides new knowledge and techniques for future development of liposome-based drug delivery systems, peptide-based therapeutics and increase our understanding of peptide-lipid interactions.