Nose-to-brain delivery of a novel boronated curcuminoid via cyclodextrins: Biodistribution toward potential BNCT applications in Alzheimer's disease.

This study investigates the selective accumulation of a boronated monocarbonyl curcuminoid (BMAC-9) complexed with β-cyclodextrins in the amyloid-rich brain regions of APP/PS1dE9 transgenic mice, an established model of Alzheimer's disease, compared to C57BL/6 healthy mice. The goal is to develop and evaluate a novel delivery system for the boronated curcuminoid BMAC-9 and to determine whether the resulting boron concentrations in the brain, particularly in the cortex and hippocampus, which are typically enriched in amyloid plaques in patients with Alzheimer's disease, could reach levels potentially suitable for Boron Neutron Capture Therapy (BNCT). Physicochemical characterization displayed that BMAC-9 has a logD of 3.45 at both physiological (7.4) and nasal (5.5) pH, suggesting good membrane permeability but poor aqueous solubility. To optimize delivery and facilitate blood-brain barrier (BBB) crossing, inclusion complexes were formulated using hydroxypropyl-β-cyclodextrin (HP-β-CD) and a cationic cyclodextrin polymer (TMA-poly-β-CD). These systems, exhibiting stability constants in the 103-105 M-1 range, significantly enhanced drug solubility. In vitro assays on SH-SY5Y cells demonstrated low cytotoxicity at short incubation times confirming that drug release and cellular uptake depend on CD binding affinity. In vivo biodistribution analysis through boron quantification by ICP-MS in C57BL/6 mice exhibit that intranasal administration achieves effective brain targeting while reducing systemic exposure compared to the intravenous one. Interestingly, the BMAC-9/HP-β-CD complex showed selective accumulation in Aβ plaque-rich brain areas only in APP/PS1dE9 transgenic mice. This selectivity is crucial for BNCT efficacy and offers a promising solution to the persistent challenge of targeted drug delivery in neurodegenerative diseases.