Drug delivery strategies to cross the blood-brain barrier in Alzheimer's disease: a comprehensive review on three promising strategies

The field of Alzheimer's disease (AD) drug development is rapidly changing, with two anti-amyloid monoclonal antibodies (mAbs) having received Food and Drug Administration (FDA) approval, additionally many compounds are in the pipeline. A major obstacle for novel AD therapeutics is the blood-brain barrier (BBB), which restricts passage of particles larger than 400-500 Da. It is estimated that only ∼0.1 % of mAbs, being ∼150 kDa, passes the BBB, which greatly hampers the efficacy of treatment. To enhance treatment efficacy and to lower the drug dose needed, mechanisms that effectively increase drug delivery across the BBB are urgently sought for. This narrative review describes three promising strategies to enhance drug delivery across the BBB in AD: focused ultrasound (FUS) with microbubbles, receptor-mediated transcytosis (RMT) and delivery using nanoparticle carrier systems. FUS and RMT have shown promising preclinical results and are now being tested in humans whereas nanoparticle carrier systems still need further preclinical validation before clinical application in humans. 89Zr-Immuno-PET provides a unique opportunity to noninvasively monitor and quantitatively assess novel brain delivery methods.