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@PHDTHESIS{Kostyurina:968858,
author = {Kostyurina, Ekaterina},
othercontributors = {Förster, Stephan Friedrich and Richtering, Walter},
title = {{A}lternating amphiphilic polymers : from gels and micelles
to translocation through lipid membranes},
school = {RWTH Aachen University},
type = {Dissertation},
address = {Aachen},
publisher = {RWTH Aachen University},
reportid = {RWTH-2023-08845},
pages = {1 Online-Ressource : Illustrationen, Diagramme},
year = {2023},
note = {Veröffentlicht auf dem Publikationsserver der RWTH Aachen
University; Dissertation, RWTH Aachen University, 2023},
abstract = {Amphiphilic polymers possess both hydrophobic and
hydrophilic properties, which make them able to
self-assemble in aqueous solutions, be surface active and
have simultaneous solubility in polar and non-polar
solvents. Therefore, they find various applications, also in
industry, in different areas like detergency, agriculture,
food, material engineering or pharmaceutics. In experimental
studies, statistical copolymer or block copolymer
architectures are usually investigated, because of their
ease of synthesis or their structural analogy to
surfactants. A copolymer structure that links the two
architectures is an alternating copolymer, which is easily
accessible by polycondensation reactions. Using alternating
hydrophilic and hydrophobic building blocks with varying
lengths allows a systematic variation between statistical
and multi-block architectures. In this project, the
alternating amphiphilic polymers (AAP) were broadly and
systematically studied with respect to their thermodynamic
characteristics and structure formation in water and in an
application to translocation through lipid membranes. Most
of the AAPs used in this work were synthesized as polyesters
from hydrophobic dicarboxylic acids and hydrophilic
polyethylene glycol (PEG) units. These polymers possess a
lower critical solution temperature (LCST) behavior in
water, where the critical temperature can be varied in the
range from 0 to 100oC by adjusting the lengths of
hydrophobic and hydrophilic units. Moreover, the same LCST,
which can be used as a measure for the overall polymer
polarity, can be achieved by different combinations of unit
lengths. In this way, the polarity profile along the polymer
chain can be changed from a more homogeneous to a more
alternating one. Depending on the overall polarity and on
the polarity profile the AAPs can be dissolved in water as
free chains, form micelles, gels, or ordered crystalline
phases. These structures were investigated by small angle
x-ray and neutron scattering and a qualitative phase diagram
which represents the structures as a function of the
hydrophobic and hydrophilic unit lengths was constructed.
The micelles formed by the AAP have a pronounced core
constructed by the hydrophobic domains embedded in a PEG
rich and water poor matrix, whereas the micellar shell
consists of a smaller number of PEG end groups or internal
PEG units forming loops. Such micelles differ structurally
from micelles formed by block copolymers or surfactants,
where the core is formed exclusively by the hydrophobic
units. The AAP gels are formed by interconnected micellar
structures, which make the gel mechanically stable and can
arrange in a crystalline order at high concentrations. The
ability to tune the AAP polarity allows achieving polymers
which are simultaneously soluble in water and non-polar
environments as, for example, the interior of lipid
membranes. Water soluble AAPs having such a balanced
polarity can passively translocate lipid membranes, which
was extensively studied in this thesis. The translocation
properties were systematically studied by time-resolved
Pulsed Field Gradient (PFG) NMR using large unilamellar
vesicles (LUV) as model membranes. The restricted LUV inner
volume allows to access independently adsorption and
desorption rates, as well as the concentration of the
translocating species in the membrane. It was found that the
translocation process consists of a relatively fast membrane
saturation with the polymers and a slow desorption process.
The translocation time varies from minutes to hours
depending on polymer and lipid composition, polymer
molecular weight, and temperature. On the basis of these
measurements a basic thermodynamic model of the
translocation process was developed. Neutron reflectometry
(NR) measurements proved that the AAP having short
hydrophobic/hydrophilic units are located mainly in the
hydrophobic interior of the membrane. The concentration in
the membrane calculated from the NR study was similar to the
one obtained by PFG NMR. Using fluorescent microscopy on
giant unilamellar vesicles the ability of transferring a
hydrophobic molecule through lipid membranes was proved. The
ability of the AAPs to translocate and transfer molecules
through lipid membranes can be important for biomedical
applications. Therefore, potential cell toxicity properties
of the AAPs were tested with living HeLa cells. The AAPs
synthesized as polyesters showed no visible effect on the
viability of these cells. Therefore, as the next step, in
vivo translocation studies were performed using a
fluorescently labeled AAP. The translocation through the
plasma membrane of four different cell types was proved in a
series of fluorescence microscopy measurements. The ability
to tune the AAP composition in a wide range by still
maintaining the translocation properties makes these
polymers very interesting for biomedical applications.},
cin = {155710 / 150000},
ddc = {540},
cid = {$I:(DE-82)155710_20190327$ / $I:(DE-82)150000_20140620$},
typ = {PUB:(DE-HGF)11},
doi = {10.18154/RWTH-2023-08845},
url = {https://publications.rwth-aachen.de/record/968858},
}
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