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Breaching the blood brain barrier to improve treatment of brain tumors

Posted January 21, 2014

The effectiveness of most cancer treatments targeting the central nervous system (CNS) has been limited due to body’s own defenses, particularly the blood brain barrier, which is difficult to breach for most conventional therapies. Therefore, attempts have been made to find drugs and delivery systems that could overcome these limitations and increase the treatability of brain tumors.

Credit: Wikimedia Commons

Credit: Wikimedia Commons

For the first time, scientists at the University of Chicago showed that intranasal administration of stem cell-based therapeutics may be effective in breaching the blood brain barrier and treating gliomas – the most common type of brain tumor – in mice.

The new research, due to be published in Molecular Therapy, demonstrates repeated administration of mesenchymal stem cells expressing TNF-related apoptosis-inducing ligand (TRAIL) through the nasal cavity results in effective penetration into the brain and significantly prolongs the survival of mice with experimental tumors.

TRAIL-expressing mesenchymal cells were found to penetrate the brain from the nasal cavity and migrate towards the tumor, as well as accumulate in several regions of the CNS, including the cerebellum. This findings suggest that this method may be effective for treating medulloblastomas and other cerebellar tumors, which are particularly common in children.

It should be noted that further enrichment with stem cells could be achieved in conjunction with radiation treatment, suggesting the compatibility with conventional anti-cancer therapies.

TRAIL therapy has been demonstrated to promote apoptosis (programmed cell death) in a range of tumors, including the aggressive and often inoperable gliomas. However, the efficacy of treatment has been limited due to lack of an efficient delivery system.

The intravenous drug injection provides only limited penetration into the CNS due to the blood brain barrier. In fact, stem cells have been shown to accumulate in the lungs and other organs instead, with only a small part of cells reaching the target.  While direct intracranial inoculation is also possible, the brain surgery itself is an invasive and risky procedure. Moreover, surgical delivery poses a risk of damage to the surrounding brain tissue and is not an option for patients with inoperable brain tumors.

Other attempts to breach the body’s defenses and enter the CNS have included intra-arterial delivery, or disruption of parts or all of blood brain barrier. Unfortunately, these methods have been associated with increased mortality rates due to impaired blood flow to the brain, and greater susceptibility of the CNS to toxins and pathogens.

In contrast, intranasal administration represents a non-invasive delivery method, effective in breaching the blood brain barrier and delivering the drug without introducing major complications, such as embolisms or infarctions associated with intravascular delivery. Moreover, the nasal delivery allows for multiple courses of treatment in contrast to surgical options, enhancing enrichment with stem cells and improving the chances of patient recovery.

Used alone or in combination with conventional cancer therapies, the intranasal stem cell delivery has a potential of becoming a highly efficient treatment for malignant gliomas, as well as other types of brain tumors, which are hard to treat due to the inability to breach the blood brain barrier.


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