Nose-to-brain delivery: A comparative study between carboxymethyl chitosan based conjugates of dopamine

Abstract

Herein, the synthesis of a novel polymeric conjugate N,O-CMCS-Dopamine (DA) based on an amide linkage is reported. The performances of this conjugate were compared with those of an analogous N,O-CMCS-DA ester conjugate previously studied (Cassano et al., 2020) to gain insight into their potential utility for Parkinson's disease treatment. The new amide conjugate was synthesized by standard carbodiimide coupling procedure and characterized by FT-IR, ¹H NMR spectroscopies and thermal analysis (Differential Scanning Calorimetry). In vitro mucoadhesive studies in simulated nasal fluid (SNF) evidenced high adhesive effect of both ester and amide conjugates. Results demonstrated that the amide conjugate exerted an important role to prevent DA spontaneous autoxidation both under stressed conditions and physiological mimicking ones. MTT test indicated cytocompatibility of the amide conjugate with Olfactory Ensheating Cells (OECs), which were shown by cytofluorimetry to internalize efficiently the conjugate. Overall, among the two conjugates herein studied, the N,O-CMCS-DA amide conjugate seems a promising candidate for improving the delivery of DA by nose-to-brain administration.

Keywords: 4-Dimethylaminopyridine (Compound CID 14284); Chitosan (Compound CID: 129662530); Cytotoxicity; Dimethylsulfoxide (Compound CID: 21584481); Dopamine; Dopamine hydrochloride (Compound CID: 65340); Hydrogen peroxide (Compound CID: 22326046); Mucoadhesion; N,N′-diisopropyl-carbodiimide (Compound CID: 12734); N,O-carboxymethyl chitosan–Dopamine amide conjugate, Hydroxyethyl cellulose (Compound CID: 4327536); Oxidative stability; Polymeric conjugates; Potassium Bromide (Compound CID: 253877); Sodium Sulphate (Compound CID: 516914); Uptake by OEC cells.