Development and neuroprotective testing of nanocarrier formulations for intranasal administration of curcumin derivatives CNB-001, J-147 and T-006

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Curcumin is a natural compound with anti-inflammatory, anti-oxidant and neuroprotectivecharacteristics. It attenuates mitochondrial dysfunction and reduces damage in adult andneonatal ischemia/reperfusion and inflammation models. The major limitation to clinicalimplementation of curcumin is its extremely low water-solubility (0.0004mg/ml) andbioavailability, the lack of identified molecular target and its pan essay interferencecharacteristics. CNB-001, J-147 and T-006 are synthetic curcumin analogs, thus allowingconsistency in production and purity. Although all three derivatives have better characterizedmolecular targets and are already trialed in neurodegeneration and stroke, they possess lowwater solubility and dissolve in DMSO, which is toxic for humans. Additionally, they have beenapplied orally or intravenously, which limits delivery to the brain through systemicelimination, and intranasal route of administration has not been implemented. Intranasalapplication is non-invasive, allows penetration through the blood brain barrier, it is quicker forbrain delivery through the trigeminal and olfactory routes, and by-passes peripheralelimination. Moreover, intranasal delivery is 10-fold more effective than systemicadministration and is thus more clinically relevant. This project aims to repurpose drugs thatare already in clinical testing and to develop novel nanoparticle formulations of CNB-001,J-147 and T-006 for minimally invasive intranasal application.The project will assess in vivo the pharmacokinetics of the most successful formulationsgenerated and tested in vitro for toxicity in the rotation project. Serum and brainconcentration of CNB-001, J-147 and T-006 post-intranasal administration of the nanoparticleformulations applied in naïve neonatal and adult mice will be assessed through HPLC.The formulations with best pharmacokinetics for each derivative will be histologically andbehaviourally assessed for short- and long-term in vivo neuroprotection when appliedintranasally in mouse models of neonatal hypoxia-ischaemia (Rocha-Ferreira et al., 2019) andadult facial nerve axotomy, where previously the Hristova lab has observed neuroprotectionwith systemic curcumin administration.