Strategies to enhance the distribution of nanotherapeutics in the brain

Convection enhanced delivery (CED) provides a powerful means to bypass the blood-brain barrier and drive widespread distribution of therapeutics in brain parenchyma away from the point of local administration. However, recent studies have detailed that the overall distribution of therapeutic nanoparticles (NP) following CED remains poor due to tissue inhomogeneity and anatomical barriers present in the brain, which has limited its translational applicability. Using probe NP, we first demonstrate that a significantly improved brain distribution is achieved by infusing small, non-adhesive NP via CED in a hyperosmolar infusate solution. This multimodal delivery strategy minimizes the hindrance of NP diffusion imposed by the brain extracellular matrix and reduces NP confinement within the perivascular spaces. We further recapitulate the distributions achieved by CED of this probe NP using a most widely explored biodegradable polymer-based drug delivery NP. These findings provide a strategy to overcome several key limitations of CED that have been previously observed in clinical trials.