Kang_2024_Theranostics_14_6708

Rationale: Recent studies have demonstrated the direct connections between the skull bone marrow, meninges, and brain. In an effort to explore these connections for the purpose of brain drug delivery, we previously proposed the direct application of CNS drugs into the diploic space between the outer and inner cortex of the skull, namely, intracalvariosseous administration (ICO). It was successfully demonstrated that small molecular to large colloidal drugs can readily reach the brain after ICO in mice and rabbits. Here, we report that a single ICO of donepezil microspheres protects cognitive impairment in Alzheimer mouse models over a month-long period. Methods: Donepezil-loaded long-acting microspheres (DPZ@LAM) were prepared with biodegradable poly(DL-lactide-co-glycolide) (PLGA). Pharmacokinetic study and behavioral test were performed to determine the brain exposure and therapeutic effects after ICO of DPZ@LAM in scopolamine-induced memory-deficient mice. Results: DPZ@LAM were capable of a month-long and precisely controlled drug release. After a single ICO of DPZ@LAM, DPZ concentration in brain sustained above the effective therapeutic levels for four weeks. The long-lasting brain exposure also led to significantly recovered cognitive function in scopolamine-induced memory-deficient mice, along with decreased acetylcholinesterase activity and increased brain-derived neurotrophic factor. Conclusions: ICO allows for BBB-bypassing brain drug delivery through the direct connection between the skull bone marrow and brain, providing an alternative approach for the treatment of neurodegenerative diseases with otherwise BBB impermeable CNS drugs.