Manipulation of olfactory tight junctions using papaverine to enhance intranasal delivery of gemcitabine to the brain

Context: Delivery of drugs from the nasal cavity to the brain is becoming more widely accepted, due to the non-invasive nature of this route and the ability to circumvent the blood brain barrier (BBB). Objective: Because of similarities in the proteins comprising the olfactory epithelial tight junction (TJ) proteins and those of the BBB, we sought to determine whether papaverine (PV), which is known to reversibly enhance BBB permeability, could increase the delivery of intranasally administered gemcitabine to the central nervous system in rats. Experimental methods: Included intranasal administration of gemcitabine, fluorescein isothiocyanate- dextran beads and PV, histopathology, immunostaining, RT-PCR, western blot analysis, immunofluorescence localization, spectrofluorometric analysis, in vivo brain microdialysis, HPLC analysis and in vitro gemcitabine recovery. Results and discussion: PV transiently decreased the levels and altered immunolocalization of the TJ protein phosphorylated-occludin in the olfactory epithelium, while causing an approximately four-fold increase in gemcitabine concentration reaching the brain. The enhanced delivery was not accompanied by nasal epithelial damage or toxicity to distant organs. Conclusions: The ability to transiently and safely increase drug delivery from the nose to the brain represents a non-invasive way to improve treatment of patients with brain disorders.