Preparation of novel tissue acidosis-responsive chitosan drug nanoparticles: Characterization and in vitro release properties of Ca2+ channel blocker nimodipine drug molecules

Janovák, László and Turcsányi, Árpád and Bozó, Éva and Deák, Ágota and Mérai, László and Sebők, Dániel and Juhász, Ádám and Csapó, Edit and Farkas, Eszter and Dékány, Imre and Bari, Ferenc (2018) Preparation of novel tissue acidosis-responsive chitosan drug nanoparticles: Characterization and in vitro release properties of Ca2+ channel blocker nimodipine drug molecules. EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES, 123. pp. 79-88. ISSN 0928-0987

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Abstract

The pH-responsive intelligent drug release facility of hydrophobically modified chitosan nanoparticles (Chit NPs) (d = 5.2 +/- 1.1 nm) was presented in the case of poorly water soluble Ca2+ channel blocker nimodipine (NIMO) drug molecules. The adequate pH-sensitivity, i.e. the suitable drug carrier properties of the initial hydrophilic Chit were achieved by reductive amination of Chit with hexanal (C6(-)) and dodecanal (C12(-)) aldehydes. The successful modifications of the macromolecule were evidenced via FTIR measurements: the band appearing at 1412 cm(-1) (C-N stretching in aliphatic amines) in the cases of the hydrophobically modified Chit samples shows that the C-N bond successfully formed between the Chit and the aldehydes. Hydrophobization of the polymer unambiguously led to lower water contents with lower intermolecular interactions in the prepared hydrogel matrix: the initial hydrophilic Chit has the highest water content (78.6 wt%) and the increasing hydrophobicity of the polymer resulted in decreasing water content (C-6-chit: 74.2 wt% and C-12-chit: 47.1 wt%). Furthermore, it was established that the length of the side chain of the aldehyde influences the pH-dependent solubility properties of the Chit. Transparent homogenous polymer solution was obtained at lower pH, while at higher pH the formation of polymer (nano)particles was determined and the corresponding cut-off pH values showed decreasing tendency with increasing hydrophobic feature (pH = 7.47, 6.73 and 2.49 for initial Chit, C-6-chit and C-12-chit, respectively). Next the poorly water soluble NIMO drug was encapsulated with the C-6-chit with adequate pH-sensitive properties. The polymer-stabilized NIMO particles with 10 wt% NIMO content resulted in stable dispersion in aqueous phase, the formation of polymer shell increased in the water solubility/dispersibility of the initial hydrophobic drug. According to the drug release experiments, we clearly confirmed that the encapsulated low crystallinity NIMO drug remained closed in the polymer NPs at normal tissue pH (pH = 7.4, PBS buffer, physiological condition) but at pH < 6.5 which is typical for seriously ischemic brain tissue, 93.6% of the available 0.14 mg/ml NIMO was released into the buffer solution under 8 h release time. According to this in vitro study, the presented pH-sensitive drug carrier system could be useful to selectively target ischemic brain regions characterized by acidosis, to achieve neuroprotection at tissue zones at risk of injury, without any undesirable side effects caused by systemic drug administration.

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