Synthesis and characterization of chitosan-grafted-dopamine based micelles as multifunctional nanomedicines for Parkinson's disease treatment by intranasal administration.

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The main aim of this work was to synthesize new chitosan amphiphilic derivatives able to self-assembly encapsulating substances acting at different target sites implicated in Parkinson disease (PD). For this purpose, O-carboxymethyl-chitosan (O-CMCS) was grafted with dopamine (DA) exploiting a carbodiimide mediated coupling reaction using different polymer/DA weight ratios. The structural characterization of the resulting O-CMCS-g-DA conjugates was carried out by spectral (i.e., ì FT-IR, 1H-NMR spectroscopy) and potentiometric titrations. The physicochemical characterization of these conjugates was performed by thermal analysis, scanning electron microscopy coupled with energy dispersive X-ray spectroscopy. The in vitro DA release was carried out in simulated nasal fluid showing in any case a sustained release of the neurotransmitter. The amphiphilic O-CMCS-g-DA conjugate at highest substitution degree was allowed to form micelles using the dialysis method. The Critical Micellar Concentration of such micelles was determined by the conductometric method and resulted of 1 × 10- 4 mg/mL Quercetin (QUE), selected as hydrophobic antioxidant model drug, was encapsulated into the core of these micelles with an efficiency of 18%. From a biological point of view, none of the O-CMCS-g-DA conjugates was cytotoxic against the target neuronal SH-SY5Y cells. Moreover, all the O-CMCS-g-DA conjugates were able to modulate neuroinflammation as demonstrated by mRNA expression level analysis. Therefore, these O-CMCS-g-DA based micelles showed a great potential as multifunctional nanomedicines for brain delivery by intranasal route of a lipophilic antioxidant involved in the oxidative stress together with the neurotransmitter DA exploiting a delivery system with modulating properties of neuroinflammation.

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