Abstract
A widely investigated approach to bypass the blood brain barrier is represented by the intranasal delivery of therapeutic agents exploiting the olfactory or trigeminal connections nose-brain. As for Parkinson’s disease (PD), characterized by dopaminergic midbrain neurons degeneration, currently there is no disease modifying therapy. Although several bio-nanomaterials have been evaluated for encapsulation of neurotransmitter dopamine (DA) or dopaminergic drugs in order to restore the DA content in parkinsonian patients, the premature leakage of the therapeutic agent limits this approach. To tackle this drawback, we undertook a study where the active was linked to the polymeric backbone by a covalent bond. Thus, novel nanoparticles (NPs) based on N,O-Carboxymethylchitosan-DA amide conjugate (N,O-CMCS-DA) were prepared by the nanoprecipitation method and characterized from a technological view point, cytotoxicity and uptake by Olfactory Ensheating Cells (OECs). Thermogravimetric analysis showed high chemical stability of N,O-CMCS-DA NPs and X-ray photoelectron spectroscopy evidenced the presence of amide linkages on the NPs surface. MTT test indicated their cytocompatibility with OECs, while cytofluorimetry and fluorescent microscopy revealed the internalization of labelled N,O-CMCS-DA NPs by OECs, that was increased by the presence of mucin. Altogether, these findings seem promising for further development of N,O-CMCS-DA NPs for nose-to-brain delivery application in PD.
Highlights
It is commonly accepted that the main obstacle for drug delivery in therapeutic concentrations to the brain is constituted by the blood brain barrier (BBB), which maintains the brain homeostasis and prevents the entry of substances that can cause neuronal damage [2]
Dopamine hydrochloride (DAHCl), porcine stomach mucin Polyvinylalcohol (PVA, polymerization degree 500), Fluorescein 5(6)-isothiocyanate (FITC) and PBS were supplied by Sigma-Aldrich (Milan, Italy)
NPs arising from N,O-CMCS conjugated to small molecules (DA or FITC) were lower in size than the unconjugated ones (i.e., N,O-CMCS NPs) which resulted the biggest (252 ± 33 nm/289 ± 50 nm and 608 ± 58 nm, respectively)
Summary
It is commonly accepted that the main obstacle for drug delivery in therapeutic concentrations to the brain is constituted by the blood brain barrier (BBB), which maintains the brain homeostasis and prevents the entry of substances that can cause neuronal damage [2]. This obstructing effect of the BBB is due to brain capillary endothelial cells, which limit the transcellular transport, as well as to the tight junctions between cells, that restrict the paracellular transport [3]. In the case of NDs the BBB, even though compromised and more permeable, is still
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