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

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 Ca 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 (C-) and dodecanal (C-) aldehydes. The successful modifications of the macromolecule were evidenced via FTIR measurements: the band appearing at 1412 cm (CN stretching in aliphatic amines) in the cases of the hydrophobically modified Chit samples shows that the CN 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-chit.: 74.2 wt% and C-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-chit and C-chit, respectively). Next the poorly water soluble NIMO drug was encapsulated with the C-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.

The effect of synthesis conditions and tunable hydrophilicity on the drug encapsulation capability of PLA and PLGA nanoparticles

“…3B represents. This mechanism is also suitable for the encapsulation of (hydrophobic) drug particles into polymer shell [27].…”

Midkine: The Who, What, Where, and When of a Promising Neurotrophic Therapy for Perinatal Brain Injury

“…In addition, a poly(lactic-co-glycolic acid)-poly(ethylene glycol) (PLGA-PEG) nanoparticle has successfully increased the delivery of the histone deacetylase inhibitor, curcumin, to the brain in a model of term infant NE related to HI (233). An interesting biomaterials approach involves the engineering of nanoparticles to release their "cargo" in response to tissue damage-in this case-in response to acidosis in the brain subsequent to ischemia (234). This approach is valuable because it reduces possible offtarget effects of drug delivery.…”

Chitosan nanoparticles release nimodipine in response to tissue acidosis to attenuate spreading depolarization evoked during forebrain ischemia

“…Chitosan nanoparticle suspensioneither loaded with nimodipine (an L-type voltage-gated calcium channel blocker), or devoid of the pharmacon (i.e. vehicle)was prepared in aCSF according to Janovák et al (2018). The nanoparticle suspension with encapsulated drug was expected to release nimodipine in response to a pH shift from physiological (~pH 7.35) to acidic (~pH 6.75) (Janovák et al, 2018).…”

“…Here we set out to explore whether nimodipine can be targeted with nanoparticles selectively to brain tissue affected by ischemia, to inhibit recurrent SD events perceived to be harmful to the survival of the penumbra. We have recently constructed hydrophobized and pH-sensitive chitosan nanoparticles, which release nimodipine in response to an acidic pH shift (from pH 7.3 to~6.9), the drug release having been confirmed in suspension (Janovák et al, 2018). Decreasing pH has been utilized as the trigger of drug release from nanoparticles, because ischemia produces local tissue acidosis, which is further worsened by the occurrence of SDs (Menyhárt et al, 2017).…”

“…In the present study, we applied nimodipine associated to pH responsive chitosan nanoparticles (d = 5.2 ± 1.1 nm) (Janovák et al, 2018) to the exposed cerebral cortex of rats to investigate (i) whether tissue acidosis caused by ischemia or SD occurrence initiates drug release in the nervous tissue, and (ii) whether nimodipine administered with nanoparticles exerts its expected vasodilator and neuroprotective effect against SD propagating over the penumbra. With encouraging data in hand, we aim to build upon these results and design, in future work, an approach for the systemic administration of the pH responsive chitosan nanoparticles.…”