Cell Penetrating
Peptide (CPP)-Conjugated Desferrioxamine
for Enhanced Neuroprotection: Synthesis and in Vitro Evaluation
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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