Strategies to Enhance the Distribution of Therapeutic Nanoparticles in the Brain by Convection Enhanced Delivery

Abstract

Convection enhanced delivery (CED) is an attractive method to bypass the blood-brain barrier for therapeutic delivery to the brain as well as to facilitate widespread therapeutic distribution within brain parenchyma by creating a continuous pressure-driven bulk flow. However, rapid removal of therapeutics from the brain by the physiological clearance mechanism remains a critical challenge to achieving widespread therapeutic delivery by CED. Nanoparticle (NP)-based delivery systems that stay longer in the brain while convoying a high concentration of payloads can potentially provide widespread and efficient therapeutic delivery to the highly disseminated disease areas within the brain. In particular, we have recently demonstrated that CED of NPs designed to efficiently penetrate the highly adhesive and nanoporous brain extracellular matrix synergistically enhances the payload distribution within healthy and tumor-bearing brains. In this book chapter, we first briefly overview the mechanism and current limitations of CED, as well as strategies to maximize the CED-mediated therapeutic and/or NP delivery to the brain. We then describe a detailed methodology for preclinical CED experiments, including device/animal setup, NP preparation, tissue processing, and image/data analysis. Finally, we conclude the chapter with a few troubleshooting tips.