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

Abstract

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.

Tailoring Formulations for Intranasal Nose-to-Brain Delivery: A Review on Architecture, Physico-Chemical Characteristics and Mucociliary Clearance of the Nasal Olfactory Mucosa

“…A highly critical point in drug delivery is the low availability of drugs in the central nervous system (CNS) due to the blood-brain barrier. This barrier prevents 95% of molecules from entering the CNS by numerous tight junctions and efflux transporters [ 2 ]. Though, the blood-brain barrier is more permeable for small lipophilic molecules and provides some specific transporters, it limits severely therapies for CNS diseases [ 3 , 4 ].…”

“…Nevertheless, their presence does not directly reflect the permeability of the mucosa. Despite the presence of tight junctions, the nasal epithelia provide a low transepithelial electrical resistance (TEER) and a good permeability for drugs [ 2 ]. Manipulation of tight junctions forming the blood-brain barrier is discussed to facilitate drug delivery into the CNS.…”

“…Manipulation of tight junctions forming the blood-brain barrier is discussed to facilitate drug delivery into the CNS. But a leaky blood-brain barrier did not only enhance drug delivery, but also the risk of CNS infection and may lead to severe side effects as the increased risk of brain oedema [ 2 ]. In parallel, manipulation of tight junctions in the olfactory mucosa may also cause irreversible damage.…”

“…In parallel, manipulation of tight junctions in the olfactory mucosa may also cause irreversible damage. One of the substances with an apparent limited risk is papaverine, a vasodilator with time dependent reversible effect on tight junctions [ 2 ].…”

“…However, this hurdle may be porous, as the neuronal turnover within the olfactory epithelial layer is rather high. As described above, the olfactory neurons have a short lifetime until they undergo cell death and leave a gap [ 2 , 3 , 11 , 96 ]. The new neuron regrows in this gap, but these clefts may allow an efficient drug uptake even for larger particles.…”