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@ARTICLE{Elfgen:889730,
      author       = {Elfgen, Anne and Santiago-Schübel, Beatrix and Hupert,
                      Michelle and Schemmert, Sarah and Schartmann, Elena and
                      Tusche, Markus and Gering, Ian and Zafiu, Christian and
                      Kutzsche, Janine},
      title        = {{O}ral absorption enhancement of the amyloid-β oligomer
                      eliminating compound {RD}2 by conjugation with folic acid},
      journal      = {European journal of pharmaceutical sciences},
      volume       = {156},
      issn         = {0928-0987},
      address      = {New York, NY [u.a.]},
      publisher    = {Elsevier},
      reportid     = {FZJ-2021-00351},
      pages        = {105581 -},
      year         = {2021},
      abstract     = {Amyloid-β (Aβ) plays a central role in the development
                      and progression of Alzheimer's disease (AD) with Aβ
                      oligomers representing the most toxic species. The
                      all-d-enantiomeric peptide RD2, which recently successfully
                      completed clinical phase I, specifically eliminates Aβ
                      oligomers in vitro as well as in vivo and improves cognitive
                      deficits in various transgenic AD mouse models even after
                      oral administration. To further enhance the oral absorption
                      of RD2, folic acid has been conjugated to the d-peptide
                      promoting an endocytosis-mediated uptake via a folate
                      receptor located in the intestine. Two different conjugation
                      strategies were selected to obtain prodrugs with folic acid
                      being cleaved after intestinal absorption releasing
                      unmodified RD2 in order to enable RD2's unaltered systemic
                      efficacy. Both conjugates remained stable in simulated
                      gastrointestinal fluids. But only one of them was suitable
                      as prodrug as it was cleaved to RD2 in vitro in human blood
                      plasma and liver microsomes and in vivo in mice after
                      intravenous injection leading to a systemic release of RD2.
                      Furthermore, the conjugate's permeability in vitro and after
                      oral administration in mice was strongly enhanced compared
                      to unconjugated RD2 demonstrating the prodrug's
                      functionality. However, the conjugate seemed to have
                      impaired the mice's wellbeing shortly after oral
                      administration possibly resulting from strain-specific
                      hypersensitivity to folic acid. Nevertheless, we assume that
                      the prodrug is actually non-toxic, especially in lower
                      concentrations as verified by a cell viability test.
                      Furthermore, lower dosages can be applied with unaltered
                      efficacy due to its enhanced oral absorption.},
      cin          = {IBI-7 / ZEA-3},
      ddc          = {610},
      cid          = {I:(DE-Juel1)IBI-7-20200312 / I:(DE-Juel1)ZEA-3-20090406},
      pnm          = {5244 - Information Processing in Neuronal Networks
                      (POF4-524)},
      pid          = {G:(DE-HGF)POF4-5244},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {33035662},
      UT           = {WOS:000597224100001},
      doi          = {10.1016/j.ejps.2020.105581},
      url          = {https://juser.fz-juelich.de/record/889730},
}