Pharmacokinetic Study of Intravenous Lomustine and Intranasal Lomustine-Loaded Solusome Nanovesicle in Rats for Brain Targeting
Keywords:
Brain targeting, Glioblastoma multiforme, HPLC validation, Lomustine, Nose to brain delivery, SolusomesAbstract
Background: Glioblastoma multiforme is a Grade IV, very aggressive malignancy and the most frequent primary cancer of the central nervous system. Despite its favorable alkylating agent property and use in the treatment of GBM, the low aqueous solubility and high dose-related systemic toxicity restrict the clinical use of lomustine. Objectives: The aim of the study was to design and optimize a high-performance liquid chromatography assay to measure lomustine and to assess the pharmacokinetic properties of a novel nano-vesicular delivery system, lomustine-loaded solusomes, to estimate nose-to-brain targeting. Methods: Solosomes of lomustine were developed by the thin-film hydration method. Their ability to target the brain was tested in vivo with 84 Wistar rats. The pharmacokinetic parameters were determined after intranasal administration of solusomal formulation and compared with intravenous administration of a lomustine solution for 72 hours. Results: When delivered intranasally, lomustine-loaded solusomes achieved greatly improved brain targeting with a 2.3-fold greater maximum brain concentration (Cmax) than with intravenous delivery and a shorter time to peak concentration (Tmax). The formulation showed high targeting efficiency, with drug targeting efficiency (DTE% 486.22) and direct transport percentage (DTP% 64.8). Histopathological analysis was used to establish the preservation of the integrity of nasal mucosa, and the formulation was found to be safe and non-irritating. Conclusions: Solusomes administered through the nasal route are effective in bypassing the blood-brain barrier through olfactory and trigeminal routes. The method has proven to be an effective way of increasing concentrations of therapeutic agents in the brain without worsening the safety profile.
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