(483i) Strategies for Convection-Enhanced Drug Delivery

Convection-enhanced delivery (CED) is a novel method of delivering chemotherapeutics and other compounds to the brain for the treatment of primary brain tumors and certain neurological disorders. In CED, compounds are infused directly into the interstitium of brain tissue through a needle or cannula implanted in the brain. Because CED bypasses the blood-brain barrier, it can be used to deliver compounds that cannot be delivered to the brain by systemic means, including proteins, viral vectors, nucleotides, and molecules packaged in nanoparticles and liposomes.

The challenges in CED that we address are 1) achieving high infusion rates into the brain, and 2) controlling the spatial and temporal distribution of the infused material.  High flow rates are important, because transport of the infused compounds near the needle is dominated by convection.  For the drugs to penetrate far into the surrounding tissue, the convection rate must be sufficient to overcome the clearance of infused compounds due to a variety of elimination mechanisms.

To achieve high infusion rates into the brain, we have developed a series of microfabricated catheters containing microfluidic circuits that permit higher infusion rates and have several other advantages over needles currently used in CED.  The microfabricated devices are much smaller than needles, they can be designed to deliver several therapeutic fluids in a programmed sequence, and they can be made flexible so that they can be implanted in the brain for extended times.

To control the spatial distribution of compounds once they have been infused into the brain, we expose regions of the brain tissue to safe levels of ultrasound.  Ultrasound has been shown to increase mass transfer in tissue in several applications.  By focusing the ultrasound on particular tissue volumes, the flow of infused fluid can be directed toward specific tissue targets identified from imaging studies.  A series of experiments are described in brain phantoms and in anesthetized rodents to illustrate these CED strategies.