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@PHDTHESIS{Kostyurina:1021476,
      author       = {Kostyurina, Ekaterina and Förster, Stephan Friedrich and
                      Richtering, Walter},
      title        = {{A}lternating amphiphilic polymers : from gels and micelles
                      to translocation through lipid membranes},
      school       = {RWTH Aachen},
      type         = {Dissertation},
      address      = {Aachen},
      publisher    = {RWTH Aachen University},
      reportid     = {FZJ-2024-00769},
      pages        = {161 pages},
      year         = {2023},
      note         = {Dissertation, RWTH Aachen, 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.},
      keywords     = {Hochschulschrift (Other) / amphiphilic polymers , LCST ,
                      membrane translocation , polymeric gels , micelles (Other)},
      cin          = {JCNS-FRM-II / JCNS-1},
      cid          = {I:(DE-Juel1)JCNS-FRM-II-20110218 /
                      I:(DE-Juel1)JCNS-1-20110106},
      pnm          = {6G4 - Jülich Centre for Neutron Research (JCNS) (FZJ)
                      (POF4-6G4)},
      pid          = {G:(DE-HGF)POF4-6G4},
      experiment   = {EXP:(DE-MLZ)KWS1-20140101 / EXP:(DE-MLZ)MARIA-20140101},
      typ          = {PUB:(DE-HGF)11},
      doi          = {10.18154/RWTH-2023-08845},
      url          = {https://juser.fz-juelich.de/record/1021476},
}