title: Cell penetrating peptide (CPP)-conjugated desferrioxamine for enhanced neuroprotection: synthesis and in vitro evaluation.
abstract: Iron overload causes progressive and sometimes irreversible damage due to accelerated production of reactive oxygen species. Desferrioxamine (DFO), a siderophore, has been used clinically to remove excess iron. However, the applications of DFO are limited because of its inability to access intracellular labile iron. Cell penetrating peptides (CPPs) have become an efficient delivery vector for the enhanced internalization of drugs into the cytosol. We describe, herein, an efficient method for covalently conjugating DFO to the CPPs TAT(47-57) and Penetratin. Both conjugates suppressed the redox activity of labile plasma iron in buffered solutions and in iron-overloaded sera. Enhanced access to intracellular labile iron compared to the parent siderophore was achieved in HeLa and RBE4 (a model of blood-brain-barrier) cell lines. Iron complexes of both conjugates also had better permeability in both cell models. DFO antioxidant and iron binding properties were preserved and its bioavailability was increased upon CPP conjugation, which opens new therapeutic possibilities for neurodegenerative processes associated with brain iron overload.
authors.affiliation: Departamentos de Química Fundamental e de ‡Bioquímica, Instituto de Química, Universidade de São Paulo , Av. Lineu Prestes 748, 05508-000, São Paulo, Brazil.
authors.forename: Dibakar
authors.initials: D
authors.lastname: Goswami
authors.forename: M Teresa
authors.initials: MT
authors.lastname: Machini
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Silvestre
authors.forename: Cassiana S
authors.initials: CS
authors.lastname: Nomura
authors.forename: Breno Pannia
authors.initials: BP
authors.lastname: Esposito
mesh_terms: D000595:Amino Acid Sequence; D000975:Antioxidants / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D001059:Apoproteins / Q000378:metabolism; D001667:Binding, Competitive; D057846:Cell-Penetrating Peptides / Q000138:chemical synthesis* / Q000737:chemistry* / Q000378:metabolism; D060326:Chemistry Techniques, Synthetic; D003676:Deferoxamine / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D004337:Drug Carriers / Q000138:chemical synthesis* / Q000737:chemistry* / Q000378:metabolism; D019793:Fluorescein / Q000378:metabolism; D005452:Fluoresceins / Q000378:metabolism; D015696:Gene Products, tat / Q000737:chemistry; D006367:HeLa Cells; D006801:Humans; D007501:Iron / Q000378:metabolism; D008969:Molecular Sequence Data; D018696:Neuroprotective Agents / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D010539:Permeability; D014168:Transferrin / Q000378:metabolism
chemical_list: D000975:Antioxidants; D001059:Apoproteins; D057846:Cell-Penetrating Peptides; D004337:Drug Carriers; D005452:Fluoresceins; D015696:Gene Products, tat; D018696:Neuroprotective Agents; D014168:Transferrin; C028284:apotransferrin; D007501:Iron; D003676:Deferoxamine; D019793:Fluorescein; C007740:fluorexon