Posted by From curcuminoid solubilization to potential boron neutron capture therapy for Alzheimer’s disease
What if a cyclodextrin could help take a boron-containing drug from the nose directly toward the brain and potentially toward amyloid plaques?
A new study published in the Journal of Controlled Release explores exactly this possibility. Researchers from Italy investigated a novel boronated monocarbonyl curcuminoid, BMAC-9, as a potential agent for boron neutron capture therapy (BNCT) targeting Alzheimer’s disease. BMAC-9 is highly lipophilic, with a logD of 3.45, and its poor aqueous solubility makes formulation and delivery challenging.
The authors formulated BMAC-9 using two β-cyclodextrin-based systems:
- hydroxypropyl-β-cyclodextrin (HP-β-CD), and
- a cationic cyclodextrin polymer, TMA-poly-β-CD (prepared by CycloLab).
The resulting inclusion complexes displayed stability constants in the 10³–10⁵ M⁻¹ range, substantially improving the aqueous solubility of BMAC-9. But the most interesting aspect is that the cyclodextrins were not merely used to make an insoluble molecule easier to formulate.
Their interaction with BMAC-9 also influenced drug release and cellular uptake. In vitro experiments with SH-SY5Y cells indicated that these processes were dependent on the affinity between the drug and the cyclodextrin system. In other words, the same molecular recognition that helps solubilize BMAC-9 can also become part of the mechanism controlling its biological availability.
From nose to brain
The researchers then took advantage of another attractive feature of intranasal administration: the possibility of delivering molecules to the brain while reducing exposure to the peripheral circulation.
In mice, boron concentrations were quantified by ICP-MS after intranasal and intravenous administration. The intranasal route produced effective brain delivery while reducing systemic exposure compared with intravenous administration.
In the APP/PS1dE9 mouse model of Alzheimer’s disease, the BMAC-9/HP-β-CD complex showed selective accumulation in brain regions rich in amyloid-β plaques. This effect was observed specifically in the transgenic animals and not in healthy C57BL/6 mice.
BNCT relies on bringing sufficient amounts of boron-10 into target cells or tissues. Irradiation with neutrons then triggers the B → Li nuclear reaction, producing high-energy particles over very short distances.
The authors propose that selective accumulation of the BMAC-9/HP-β-CD complex in amyloid-rich regions could potentially provide a route toward localized BNCT in Alzheimer’s disease. Importantly, however, the study is still preclinical: the experiments were performed in cell cultures and mouse models, and the findings demonstrate a promising delivery concept rather than an established Alzheimer’s treatment.
Reference:
Alberti D. et al., “Nose-to-brain delivery of a novel boronated curcuminoid via cyclodextrins: Biodistribution toward potential BNCT applications in Alzheimer’s disease”, Journal of Controlled Release 398 (2026) 115270. DOI: 10.1016/j.jconrel.2026.115270.
Image courtesy: Hanna Koivonoro, Neutron Therapeutics