Zitong Shao1,2, Jiahui Deng1,2, Ho Wan Chan1 & Shing Fung Chow1,2
1Department of Pharmacology and Pharmacy, The University of Hong Kong, Hong Kong SAR China
2Advanced Biomedical Instrumentation Centre, Hong Kong Science Park, Shatin, Hong Kong SAR China
Summary
Ischemic stroke causes rapid neuronal damage within seconds, particularly during the hyperacute phase, leading to high mortality and long-term disability. Current reperfusion therapies, such as tissue plasminogen activator and endovascular thrombectomy, are limited by issues of accessibility and the urgency of administration. Despite extensive neuroprotective research, the blood-brain barrier (BBB) remains a major obstacle to effective neurotherapeutic delivery. Nose-to-brain delivery offers a promising alternative by bypassing the BBB through direct olfactory pathways, especially when combined with nanotechnology. Engineered nanoparticles can facilitate rapid mucosal transport and targeted cellular uptake. When formulated into stable micronized aerosol powders, these nanoparticles can achieve consistent olfactory deposition and controlled drug release, enhancing delivery efficacy.
Recent studies identified cholecalciferol (Vitamin D3), a safe endogenous prohormone, as an effective neuroprotective agent due to its multi-target, multi-phase mechanisms against stroke pathology. To ensure efficient nose-to-brain delivery, cholecalciferol nanosuspension was spray-dried with methylcellulose (MC) and polyvinylpyrrolidone K30 (PVP) to produce a nanoagglomerate powder. The resulting formulation preserved nanoparticle integrity, evidenced by a redispersibility index (RdI) of 1.36 ± 0.05, and achieved a satisfactory olfactory deposition fraction of 18.47 ± 1.55%. In vivo efficacy evaluation in a mouse stroke model demonstrated significant restoration of neurological functions following a single intranasal administration of 2 mg/kg.
These findings indicate that cholecalciferol nanoagglomerate powders delivered via the intranasal route represent a rapid, non-invasive, and effective therapeutic strategy for ischemic stroke. This innovative approach has the potential to address current clinical challenges, particularly in prehospital settings as a first-aid therapy, thereby improving patient outcomes.