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Preparation and characterization of nanometer-sized mechano-responsive liposomes for physically-triggered drug delivery

Matviykiv, Sofiya. Preparation and characterization of nanometer-sized mechano-responsive liposomes for physically-triggered drug delivery. 2018, Doctoral Thesis, University of Basel, Faculty of Science.

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Official URL: http://edoc.unibas.ch/diss/DissB_13310

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Abstract

Cardiovascular diseases remain the leading causes of death worldwide, accounting for 17.7 million deaths every year - 31% of all global deaths. Atherosclerosis is an underlying disease process in blood vessels that leads to the accumulation of cholesterol plaques and a narrowing of the arterial lumen. If the plaque bursts, the components are flushed into the bloodstream, triggering intravascular thrombosis and leading to vascular occlusions. Heart attack or stroke are the most dangerous medical consequences of this. In such an event, time is of utmost importance because the infarcted organ suffers from necrosis without re-establishment of blood perfusion within a few minutes. Currently, emergency treatment provided in the ambulance involves intravenous injection of vasodilators that act systemically to dilate blood vessels and re-establish blood supply. However, this works systemically and even at a low dose lead to peripheral resistance decrease of the vessels and thereby hypotension. This generally inhibits the blood perfusion and thus the drug cannot work optimally at the location of the constricted vessel. Therefore, the development of a smart and effective drug delivery system, capable of releasing the drug locally, is desired. Critically constricted arteries give rise to increased wall shear stress that can be used as a physical trigger to release the therapeutics. Liposomes belong to the most attractive carriers for drug targeting in medical fields. Recently, mechano-responsive liposomes prepared from artificial phospholipids were suggested as nanocontainers for delivery and release of vasodilators at constrictions of arteries.
This thesis project gives insight into the physicochemical properties of the mechano-responsive liposomes, determines their thermal stability at physiologically relevant body temperatures, and demonstrates their in vitro immunocompatibility.
The preliminary characterization of nanometer-size liposomes is essential for the development of clinically relevant drug delivery systems. The mechano-sensitive liposomes Pad-PC-Pad and Rad-PC-Rad were studied by means of dynamic light scattering and transmission electron microscopy at cryogenic temperatures to determine size distribution and shape. In both cases, the liposomes were found to be around 100 nm in size with a variety of shapes. To prevent liposome aggregation as a consequence of the low zeta potential, a steric stabilization using polyethylene-glycol-grafted phospholipids was applied.
To ensure mechano-responsive behavior at body temperature, the liposomes’ structure should be stable at physiological and elevated body temperatures. Therefore, the structural changes of liposomes were evaluated in a temperature range from 22 to 42 °C. Small-angle neutron scattering was used to measure the radius, eccentricity, and bilayer thickness of liposomes. Pad-PC-Pad liposomes already undergo structural changes at 35 °C. Further heating to 42 °C and subsequent cooling to room temperature resulted in a decreased eccentricity by an order of magnitude and a 20% increase of bilayer thickness, indicating the loss of membrane interdigitation. Rad-PC-Rad liposomes, however, show thermal stability up to 42 °C. Thus, Rad-PC-Rad liposomes possess sufficient thermal stability for drug delivery to atherosclerotic human blood vessels.
To advance this technology towards clinical applications, the in vitro immunocompatibility of liposomes was investigated. The systemic administration of liposomes may trigger an immediate activation of the immune system, resulting in a hypersensitivity reaction. This reaction is driven by the activation of the complement system, which can stimulate the production of pro-inflammatory cytokines. Experiments demonstrated that both the Pad-PC-Pad and Rad-PC-Rad liposomal formulations exhibited low-to-moderate levels of complement proteins compared to the Food-and-Drug-Administration-approved liposomal drugs such as Doxil® and AmBisome®. Within the restricted number of individuals, one outliner was detected, suggesting that a substantially higher number of donors should be incorporated into future studies.
Advisors:Müller, Bert and Huwyler, Jörg and Willumeit-Römer, Regine
Faculties and Departments:03 Faculty of Medicine > Departement Biomedical Engineering > Imaging and Computational Modelling > Biomaterials Science Center (Müller)
05 Faculty of Science
UniBasel Contributors:Müller, Bert and Huwyler, Jörg
Item Type:Thesis
Thesis Subtype:Doctoral Thesis
Thesis no:13310
Thesis status:Complete
Bibsysno:Link to catalogue
Number of Pages:1 Online-Ressource (x, 79 Seiten)
Language:English
Identification Number:
Last Modified:23 Oct 2019 04:30
Deposited On:22 Oct 2019 13:00

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