Computer simulations and in vivo convection-enhanced delivery of fluorescent nanoparticles demonstrate variable distribution geometry

Abstract

ObjectiveConvection-enhanced delivery (CED) has emerged as a promising technique for bypassing the blood–brain barrier to deliver therapeutic agents. However, animal studies and clinical trials that utilize the technique suggest that it may require further optimization before it can be safely used in humans. In particular, while volume of distribution in the target tissue can be controlled, the geometrical spread into a desired target region is highly variable from experiment to experiment. In the present paper we have sought to characterize the non-uniform distribution geometry using fluorescent nanoparticles in both a rat model and computer simulations. MethodsUsing diffusion tensor imaging MRI data of the rat brain, we performed computer simulations of a 0.5μL/min CED infusion. A step design catheter targeting the striatum was simulated to infuse 20μL of infusate. Using the same infusion parameters, we then performed in vivo CED experiments where we infused fluorescently labeled polyethylene glycol-polylactide-polycaprolactone nanoparticles (FPNPs) into the rat striatum. Fluorescence microscopy was used to examine the distribution geometry histologically. ResultsThe computer simulations demonstrated large variations in distribution patterns when catheter placement was shifted by only 1mm. Animal infusions also exhibited highly irregular and variable distribution geometries despite the use of relatively small flow rates. ConclusionComputer simulations and repeated in vivo infusions demonstrate the difficulty of achieving desired drug distribution in target tissue. We have proposed a calculation for sphericity which, along with the ubiquitous volume of distribution measure, may prove helpful in describing distribution geometry. Taken together, our results suggest that CED's limitations must be considered and further optimization may be required before the technique sees widespread use in humans.