Dataset Information

Drug delivery in overcoming the blood-brain barrier: role of nasal mucosal grafting.

ABSTRACT: The blood-brain barrier (BBB) plays a fundamental role in protecting and maintaining the homeostasis of the brain. For this reason, drug delivery to the brain is much more difficult than that to other compartments of the body. In order to bypass or cross the BBB, many strategies have been developed: invasive techniques, such as temporary disruption of the BBB or direct intraventricular and intracerebral administration of the drug, as well as noninvasive techniques. Preliminary results, reported in the large number of studies on the potential strategies for brain delivery, are encouraging, but it is far too early to draw any conclusion about the actual use of these therapeutic approaches. Among the most recent, but still pioneering, approaches related to the nasal mucosa properties, the permeabilization of the BBB via nasal mucosal engrafting can offer new potential opportunities. It should be emphasized that this surgical procedure is quite invasive, but the implication for patient outcome needs to be compared to the gold standard of direct intracranial injection, and evaluated whilst keeping in mind that central nervous system diseases and lysosomal storage diseases are chronic and severely debilitating and that up to now no therapy seems to be completely successful.

SUBMITTER: Marianecci C

PROVIDER: S-EPMC5291459 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Drug delivery in overcoming the blood-brain barrier: role of nasal mucosal grafting.

Marianecci Carlotta C Rinaldi Federica F Hanieh Patrizia Nadia PN Di Marzio Luisa L Paolino Donatella D Carafa Maria M

Drug design, development and therapy 20170127

The blood-brain barrier (BBB) plays a fundamental role in protecting and maintaining the homeostasis of the brain. For this reason, drug delivery to the brain is much more difficult than that to other compartments of the body. In order to bypass or cross the BBB, many strategies have been developed: invasive techniques, such as temporary disruption of the BBB or direct intraventricular and intracerebral administration of the drug, as well as noninvasive techniques. Preliminary results, reported ...[more]

PMID: 28184152

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Project description:The most significant obstacle in the treatment of neurological disorders is the blood-brain barrier (BBB), which prevents 98% of all potential neuropharmaceuticals from reaching the central nervous system (CNS). Brain derived neurotrophic factor (BDNF) is one of the most intensely studied targets in Parkinson's disease (PD) as it can reverse disease progression. BDNF AntagoNAT's (ATs) are synthetic oligonucleotide-like compounds capable of upregulating endogenous BDNF expression. Despite the significant promise of BDNF AT therapies for PD, they cannot cross the blood-brain barrier (BBB). Our group has developed an innovative endonasal heterotopic mucosal grafting technique to provide a permanent method of permeabilizing the BBB. This method is based on established endoscopic surgical procedures currently used in routine clinical practice. Our overall goal for the study was to investigate the distribution and efficacy of BDNF AT's using an extra-cranial graft model in naïve rats using the innovative heterotopic mucosal engrafting technique. BDNF AT cationic liposomes (ideal size range 200-250 nm) were developed and characterized to enhance the delivery to rat brain. Uptake, distribution and transfection efficiency of BDNF AntagoNAT's in saline and liposomes were evaluated qualitatively (microscopy) and quantitatively (ELISA and AT hybridization assays) in RT4-D6P2T rat schwannoma cells and in naïve rats. In vivo therapeutic efficacy of BDNF AT's encapsulated in liposomes was evaluated in a 6-OHDA toxin model of PD using western blot and tyrosine hydroxylase immunohistochemistry. Using complimentary in vitro and in vivo techniques, our results demonstrate that grafts are capable of delivering therapeutic levels of BDNF ATs in liposomes and saline formulation throughout the brain resulting in significant BDNF upregulation in key end target regions relevant to PD. BDNF AT liposomes resulted in a better distribution in rat brain as compared to saline control. The delivered BDNF AT's encapsulated in liposomes also conferred a neuroprotective effect in a rat 6-OHDA model of PD. As a platform technique, these results further suggest that this approach may be utilized to deliver other BBB impermeant oligonucleotide-based therapeutics thereby opening the door to additional treatment options for CNS disease.

Dataset Information

Drug delivery in overcoming the blood-brain barrier: role of nasal mucosal grafting.

Publications

Drug delivery in overcoming the blood-brain barrier: role of nasal mucosal grafting.

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