Polymer Science

Biological activity In vitro, absorption, BBB penetration and toxicity of nanoformulation of BT44, a RET agonist with disease-modifying potential for the treatment of neurodegeneration

Authors

  • Malik Salman Haider Functional Polymer Materials, Chair for Advanced Materials Synthesis, Institute for Functional Materials and Biofabrication, Department of Chemistry and Pharmacy, Julius-Maximilians-University Würzburg, Röntgenring 11, 97070 Würzburg, Germany ,
  • Arun Kumar Mahato Laboratory of Molecular Neuroscience, Institute of Biotechnology, HiLIFE, University of Helsinki, 00014, Helsinki, Finland ,
  • Anastasiia Kotliarova Laboratory of Molecular Neuroscience, Institute of Biotechnology, HiLIFE, University of Helsinki, 00014, Helsinki, Finland ,
  • Stefan Forster Functional Polymer Materials, Chair for Advanced Materials Synthesis, Institute for Functional Materials and Biofabrication, Department of Chemistry and Pharmacy, Julius-Maximilians-University Würzburg, Röntgenring 11, 97070 Würzburg, Germany ,
  • Bettina Böttcher Biocenter and Rudolf Virchow Centre, Julius-Maximilians-University Würzburg, Haus D15, Josef-Schneider-Str. 2, 97080 Würzburg, Germany ,
  • Philipp Stahlhut Department of Functional Materials in Medicine and Dentistry, Institute of Functional Materials and Biofabrication and Bavarian Polymer Institute, Julius-Maximilians-University Würzburg, Pleicherwall 2, 97070 Würzburg, Germany ,
  • Yulia Sidorova Laboratory of Molecular Neuroscience, Institute of Biotechnology, HiLIFE, University of Helsinki, 00014, Helsinki, Finland ,
  • Robert Luxenhofer Soft Matter Chemistry, Department of Chemistry, and Helsinki Institute of Sustainability Science, Faculty of Science, University of Helsinki, PB 55, 00014 Helsinki, Finland

Abstract

BT44 is a novel, second generation glial cell line-derived neurotropic factor (GDNF) mimetic, with improved biological activity and a lead compound for the treatment of neurodegenerative disorders. Like many other small molecules, it suffers from intrinsic poor aqueous solubility, posing significant hurdles at various levels for its preclinical development and clinical translation. Herein, we report a novel poly(2-oxazoline)s (POx) based BT44 micellar nanoformulation with ultra-high drug loading capacity of 47 wt.%. The BT44 nanoformulations were comprehensively characterized by 1H-NMR spectroscopy, differential scanning calorimetry (DSC), powder X-ray diffraction (XRD), dynamic light scattering (DLS) and cryo-transmission/scanning electron microscopy (cryo-TEM/SEM). The DSC, XRD and redispersion studies collectively confirmed that the BT44 formulation can be stored as a lyophilized powder and can be redispersed when needed. The DLS further suggested that the redispersed formulation is suitable for parenteral administration (Dh ≈ 70nm). The cryo-TEM analysis revealed the presences of worm like structures. The BT44 formulation retains biological activity in immortalized cells and in cultured dopamine neurons. The micellar formulation of BT44 exhibited improved absorption and blood-brain barrier (BBB) penetration and produced no acute toxic effects in mice. In conclusion, herein, we have developed an ultra-high BT44 loaded aqueous injectable nanoformulation, which can be used to pave way for its preclinical and clinical development for the management of neurodegenerative disorders.

Content

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