Ms. Alexandra Bukchi
The treatment of diseases of the central nervous system (CNS) is highly challenging owing to the presence of the blood-brain barrier (BBB), a primary physiological barrier, which precludes the crossing of a broad spectrum of drugs into it. In this scenario, the design of novel strategies to increase drug bioavailability in the CNS is called for. Aiming to pave the way to a more efficient delivery of drugs into the CNS, a full protease-resistant peptide coined shuttle peptide that targets the transferrin receptor (TfR) highly expressed in the brain blood vessels has been designed and its ability to cross the BBB demonstrated.Polymeric micelles (PMs) are nanostructures formed by the self-assembly of polymeric amphiphiles and that display hydrophilic and hydrophobic domains. PMs have been extensively investigated to encapsulate and target poorly water-soluble drugs. In this work, we initially modified the surface of multimicellar nanoparticles (size of 200 nm) produced by the hydrophobization of a chitosan (CS) backbone with poly(methyl methacrylate) (PMMA) and poly(acrylic acid) (PAAc) with this shuttle peptide. After a comprehensive characterization of the nanoparticles, we assessed their cell compatibility and permeability in BBB endothelium monolayers in vitro. Results showed that the modification increases the apparent permeability of the nanoparticles by 4-fold. Finally, biodistribution studies upon intravenous injection to ICR male mice confirmed the ability of this peptide to increase the CNS bioavailability of the nanoparticles.