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Getting into the brain: approaches to enhance brain drug delivery

A major difficulty in treating brain tumors is overcoming the blood-brain barrier.  This is no less true with diffuse intrinsic pontine gliomas.

Unlike other areas of the body where substances can pass freely from the blood into the tissue because there are some space between the cells lining the blood vessels, in the brain movement of substances is significantly limited.  This barrier between the blood and the brain is formed by the lining cells of the vessels as well as projections from nearby astrocytes.   These two types of cells are knitted together by proteins to form what is called ‘tight junctions’.  The entire structure is called the Blood Brain Barrier (BBB).   The result is that chemicals, toxins, bacterial and other substances are often kept from getting into the brain.  Thus, it serves a daily protective function preventing substances to get to the brain.  However with disease such as brain tumors the BBB also can prevent diagnostic and therapeutic agents from reaching their target in the central nervous system.

Researchers and clinicians have developed ways to try to overcome the blood brain barrier.  Here are some examples:

  • Intrathecal/Intraventricular Administration - This is chemotherapy directed injected into the cerebral spinal fluid either through a lumbar puncture or a surgically implanted catheter.
  • Intracerebral Implants - Formation of  a cavity surgically within a tumor allows the potential to place chemotherapy wafers- such as gliadel wafers.  Several of these dime sized wafers can be placed at the time of surgery and will release the chemotherapy slowly over time (carmustine).  The advantages include a much higher concentration of chemotherapy in the brain than can be obtained over intravenous administration as well as less systemic side effects.   Gliadel is an FDA approved indication at initial and subsequent surgeries for malignant gliomas.  This is not an option for those patients who do not have surgically resectable tumor so is not available for DIPGs.

Video:  http://www.gliadel.com/consumer/about/moa_video.aspx

  • Osmotic Blood Brain Barrier Disruption (BBBD) -  With BBBD the cells of the BBB are shrunk by a concentrated sugar solution (mannitol).  This allows the barrier to open up and ten to hundred fold increase of chemotherapy to enter the brain.  A catheter is placed into one of the big arteries (usually the one in the groin called the femoral artery) and a catheter threaded up to the carotid or vertebral vessels.  The hypertonic mannitol is injected and afterwards a chemotherapeutic agent is injected.  Patients spend a few days in the hospital for each administration.  This has been attempted with DIPG tumors.

Reference: Osmotic blood-brain barrier - disruption chemotherapy for diffuse pontine gliomas
J Neurooncol. 2006 May;77(3):279-84. Epub 2005 Nov 29

  • Convection Enhanced Delivery - Convection-enhanced delivery allows for chemotherapy to get to the tumor by a surgically implanted catheter under a pressure gradient to achieve more distribution than with diffusion alone.  There has been limited experimental experience with brain tumors and one article with a DIPG.

Reference: Real-time image-guided direct convection perfusion of intrinsic brainstem lesions.
J Neurosurg. 2007 Jul;107(1):190-7.

  • Drug Carriers - Trojan horses, liposomes and nanoparticles - Most of this is in an investigational level and is not clinical relevant to brain tumors treatment at this time.  The hope is that a drug can be combined with another agent which will allow it to cross in a protected manner into the brain. Drugs can be linked to agents that normally cross into the brain. 

Reference: Getting into the Brain:  Approaches to enhance brain drug delivery CNS Drugs 2009;23(1):35-58.

Last update Feb. 22, 2009

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