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

Curcumin is a natural compound with anti-inflammatory, anti-oxidant and neuroprotective
characteristics. It attenuates mitochondrial dysfunction and reduces damage in adult and
neonatal ischemia/reperfusion and inflammation models. The major limitation to clinical
implementation of curcumin is its extremely low water-solubility (0.0004mg/ml) and
bioavailability, the lack of identified molecular target and its pan essay interference
characteristics. CNB-001, J-147 and T-006 are synthetic curcumin analogs, thus allowing
consistency in production and purity. Although all three derivatives have better characterized
molecular targets and are already trialed in neurodegeneration and stroke, they possess low
water solubility and dissolve in DMSO, which is toxic for humans. Additionally, they have been
applied orally or intravenously, which limits delivery to the brain through systemic
elimination, and intranasal route of administration has not been implemented. Intranasal
application is non-invasive, allows penetration through the blood brain barrier, it is quicker for
brain delivery through the trigeminal and olfactory routes, and by-passes peripheral
elimination. Moreover, intranasal delivery is 10-fold more effective than systemic
administration and is thus more clinically relevant. This project aims to repurpose drugs that
are 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 formulations
generated and tested in vitro for toxicity in the rotation project. Serum and brain
concentration of CNB-001, J-147 and T-006 post-intranasal administration of the nanoparticle
formulations applied in naïve neonatal and adult mice will be assessed through HPLC.
The formulations with best pharmacokinetics for each derivative will be histologically and
behaviourally assessed for short- and long-term in vivo neuroprotection when applied
intranasally in mouse models of neonatal hypoxia-ischaemia (Rocha-Ferreira et al., 2019) and
adult facial nerve axotomy, where previously the Hristova lab has observed neuroprotection
with systemic curcumin administration.