Intranasal delivery of temozolomide and desloratadine for brain tumour therapy: A cellular study on nasal epithelial toxicity, transport, and permeability

Abstract

Background

The treatment of brain tumours, particularly glioblastoma (GBM), remains a significant challenge due to limited therapeutic options and the restrictive nature of the blood-brain barrier (BBB), which contributes to inadequate effective drug delivery. Temozolomide (TMZ), the first-line chemotherapeutic agent for GBM, offers only a modest survival benefit of 14.6 months and is associated with significant systemic side effects. Intranasal drug delivery has emerged as a promising non-invasive alternative, offering direct nose-to-brain (N2B) pathways to bypass the BBB. This method enables rapid and targeted drug transport while minimising systemic toxicity.

Methods

This study investigates the potential of desloratadine (DL), a repurposed non-sedating second-generation antihistamine, to enhance the therapeutic profile of TMZ in a nasal epithelial barrier model, representing the initial point of contact for N2B drug delivery. Cellular studies were conducted to evaluate the cytotoxicity, half-maximal inhibitory concentration, combination index, epithelial integrity, and drug transport properties of TMZ and DL alone and in combination. Transepithelial electrical resistance (TEER) and permeability coefficient (P_app) assays assessed barrier integrity and drug transport across the nasal epithelial cells, while cytotoxicity studies confirmed selective targeting of nasal cells during intranasal administration without affecting bronchial cell viability.

Results

DL demonstrated significant intracellular retention in nasal epithelial cells, while TMZ exhibited efficient transport across the nasal barrier with moderate cellular retention. The combination of TMZ and DL reduced cytotoxicity in nasal epithelial cells compared to TMZ alone, suggesting DL’s protective role in mitigating TMZ-induced cytotoxic effects. TEER and P_app analyses confirmed that both agents preserved nasal epithelial integrity, supporting their compatibility with N2B delivery. The synergistic effects of the combination therapy indicate an enhanced therapeutic profile for TMZ, with reduced off-target toxicity.

Conclusion

This study highlights the potential of a TMZ-DL drug combination therapy as a novel delivery strategy for brain tumour treatment. DL not only mitigates TMZ-induced cytotoxicity but also preserves the structural and functional integrity of the nasal epithelial barrier, addressing a critical translational gap in non-invasive drug delivery for brain tumours. Future work should focus on optimising dosing regimens and validating these findings in advanced 3D nasal models to facilitate clinical translation of this innovative therapeutic approach.