Curcumin (1,7-bis-(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5dione) is a polyphenol extracted from turmeric that has long been advocated for the treatment of a variety of conditions including neurodegenerative and inflammatory disorders. Despite this promise, the clinical use of curcumin has been limited by the poor solubility and low bioavailability of this molecule. In this article, we describe a novel nanocarrier formulation comprising Pluronic-F127 stabilised D-α-Tocopherol polyethene glycol 1000 succinate nanoparticles, which were used to successfully solubilize high concentrations (4.3 mg/mL) of curcumin. Characterisation with x-ray diffraction andin vitrorelease assays localise curcumin to the nanocarrier interior, with each particle measuring <20 nm diameter. Curcumin-loaded nanocarriers (CN) were found to significantly protect against cobalt chloride induced hypoxia and glutamate induced toxicityin vitro, with CN treatment significantly increasing R28 cell viability. Using established glaucoma-relatedin vivomodels of ocular hypertension (OHT) and partial optic nerve transection (pONT), topical application of CN twice-daily for three weeks significantly reduced retinal ganglion cell loss compared to controls. Collectively, these results suggest that our novel topical CN formulation has potential as an effective neuroprotective therapy in glaucoma and other eye diseases with neuronal pathology.

This study has investigated complexation of fisetin, a natural flavonoid, with three types of cyclodextrins to improve its solubility. Sulfobutylether-β-cyclodextrin (SBE-β-CD) showed the highest complexation efficiency while maintaining the in vitro antioxidant activity of fisetin. Addition of 20%v/v ethanol in water improved the amount of solubilized fisetin in the complex 5.9-fold compared to the system containing water alone. Spray drying of fisetin-SBE-β-CD complex solution in the presence of ethanol produced a dry powder with improved aerosolization properties when delivered from a dry powder inhaler, indicated by a 2-fold increase in the fine particle fraction (FPF) compared to the powder produced from the complex solution containing water alone. The pitted morphological surface of these particles suggested a more hollow internal structure, indicating a lighter and less dense powder. Incorporation of 20%w/w leucine improved the particle size distribution of the powder and further increased the FPF by 2.3-fold. This formulation also showed an EC50 value equivalent to fisetin alone in the A549 cell line. In conclusion, an inhalable dry powder containing fisetin-SBE-β-CD complex was successfully engineered with an improved aqueous solubility of fisetin. The dry powder may be useful to deliver high amounts of fisetin to the deep lung region for therapeutic purposes.

Oxidative stress is a key mediator in the development and progression of Parkinson’s disease (PD). The antioxidant N-acetylcysteine (NAC) has generated interest as a disease-modifying therapy for PD but is limited due to poor bioavailability, a short half-life, and limited access to the brain. The aim of this study was to formulate and utilise mitochondria-targeted nanocarriers for delivery of NAC alone and in combination with the iron chelator deferoxamine (DFO), and assess their ability to protect against oxidative stress in a cellular rotenone PD model. Pluronic F68 (P68) and dequalinium (DQA) nanocarriers were prepared by a modified thin-film hydration method. An MTT assay assessed cell viability and iron status was measured using a ferrozine assay and ferritin immunoassay. For oxidative stress, a modified cellular antioxidant activity assay and the thiobarbituric acid-reactive substances assay and mitochondrial hydroxyl assay were utilised. Overall, this study demonstrates, for the first time, successful formulation of NAC and NAC + DFO into P68 + DQA nanocarriers for neuronal delivery. The results indicate that NAC and NAC + DFO nanocarriers have the potential characteristics to access the brain and that 1000 μM P68 + DQA NAC exhibited the strongest ability to protect against reduced cell viability (p = 0.0001), increased iron (p = 0.0033) and oxidative stress (p ≤ 0.0003). These NAC nanocarriers therefore demonstrate significant potential to be transitioned for further preclinical testing for PD.

Background: Encapsulation of hydrophilic drugs within liposomes can be challenging. Methods: A novel chitosan derivative, O-palmitoyl chitosan (OPC) was synthesized from chitosan and palmitoyl chloride using methane-sulfonic acid as a solvent. The success of synthesis was confirmed by Fourier transform infra-red (FT-IR) spectroscopy and proton NMR spectroscopy (H-NMR). Liposomes encapsulating ferrous sulphate as a model hydrophilic drug for intestinal delivery were prepared with or without OPC inclusion (Lipo-Fe and OPC-Lipo-Fe). Results: Entrapment of iron was significantly higher in OPC containing liposomes compared to controls. Quantitative iron absorption from the OPC liposomes was significantly higher (1.5-fold P<0.05) than free ferrous sulphate controls. Qualitative uptake analysis by confocal imaging using coumarin-6 dye loaded liposomes also indicated higher cellular uptake and internalization of the OPC-containing liposomes. Conclusion: These findings suggest that addition of OPC during liposome preparation creates robust vesicles that have improved mucoadhesive and absorption enhancing properties. The chitosan derivative OPC therefore provides a novel alternative for formulation of delivery vehicles targeting intestinal absorption.