Improving the Control of Drug Delivery to the Brain Using Electrokinetic Transport

Figure 1. Example in vivo ECED infusion of a red fluorescent cationic dye (MW 580) into the rat brain with 25 μA applied current for 45 minutes with bright field (top left) and fluorescence (bottom left). The right panels represent the fluorescence intensity along the skewed vertical (top right) and skewed horizontal (bottom right) white line scans. The scale bar is 1,000 μm.

Drug delivery to the central nervous system (CNS) presents a significant challenge to researchers and clinicians due to the blood-brain barrier. This is especially true for the delivery of small molecules, chemotherapeutics, nanoparticles, gene therapy and viral vectors, where in some cases toxic systemic levels of a drug may prevent a therapeutic level from being achieved in the CNS. Significant work is being conducted on blood-brain barrier modulation and transient disruption to allow drugs in systemic circulation to more effectively permeate into the CNS. Alternatively, stereotactic-based methods are commonly employed in clinical practice to introduce an infusion cannula to a desired anatomical location, with subsequent application of a positive pressure resulting in localized drug infusions.

Conventional pressure-driven infusion was developed to introduce locally high concentrations of macromolecules and small molecules into the CNS. This pressure-driven infusion was termed “convection-enhanced delivery (CED),” as the distribution volume observed was greater than could occur by diffusion alone in the same time frame. As this methodology was explored over the nearly two decades to the present date, the rates of infusion, infusion cannula size, concentrations of the infusate, and pre-infusion sealing times to allow accommodation of the infusion cannula were systematically studied. Despite clear efficacy in delivering localized infusates into the central nervous system, pressure-driven CED remains limited by backflow of the infusate along the implanted cannula tracts, especially at moderate to high flow rates, mass effect and edema (with or without focal neurological deficit or seizure) from large infusion volumes, and difficulty with infusion cannula placement and the directional control of infusate once inside the brain. Moreover, deep tissue deformation, separation and tearing of white matter tracts, leakage of the infusate into the cerebrospinal fluid spaces and/or prior surgical resection beds, and seepage along vascular or cannula tracts have all been documented to contribute to unpredictable intraparenchymal drug delivery.

Many of these issues can be addressed using electrokinetic transport. Electrokinetic transport in the CNS is dependent on both electroosmotic and electrophoretic transport. Electroosmosis is created by the effect of an electric field on mobile counterions that are loosely associated with the charged, porous framework containing the interstitial fluid. Because water molecules interact transiently with the moving counterions, momentum is transferred to the fluid itself resulting in bulk fluid flow. Electrophoresis is the motion of ions in an electric field resulting from the force of the potential gradient upon the charge of the ion. We demonstrated electrokinetic convection-enhanced delivery (ECED) as a viable means for delivery of locally high concentrations of macromolecules to the brain in vitro and in vivo. Directional control and quantification of the infusate in brain tissue have recently been established by our team, as shown in Figure 1. Control of directional transport was achieved over distances ranging from several hundred micrometers to more than a centimeter. Most importantly, we hope this methodology may be used to achieve new delivery profiles with the potential to improve control over infusions leading to better clinical outcomes with applications ranging from neuro-oncology to functional and restorative neurosurgery.