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. <sup>89</sup>Zr-Immuno-PET provides a unique opportunity to noninvasively monitor and quantitatively assess novel brain delivery methods.

Introduction

Purpose Drug delivery with BBB opening

Study Objective To review and evaluate three promising strategies—focused ultrasound with microbubbles, receptor-mediated transcytosis, and nanoparticle carrier systems—for enhancing delivery of therapeutics across the blood–brain barrier in Alzheimer’s disease.

Disease model Alzheimer's disease

Cargo name and characteristics Anti-amyloid monoclonal antibodies — protein therapeutics (~150 kDa mAbs); Nanoparticle carrier systems — nanoparticles for drug delivery (experimental carriers); 89Zr‑Immuno‑PET tracer — radiolabeled antibody (89Zr-labeled protein) used for imaging; General small-molecule compounds (≤400–500 Da) mentioned as therapeutic candidates

Outcomes and Safety

Summary of Outcomes Focused ultrasound (FUS) with microbubbles and receptor-mediated transcytosis (RMT) both enhanced brain delivery of large therapeutics—FUS combined with antibody delivery was associated with larger reductions in amyloid-PET burden (and an oncology study reported ~2-fold increased mAb accumulation after FUS), while RMT increased CSF-to-plasma ratios by ~8-fold; nanoparticle carriers remain preclinical. The paper did not test or report specific successful FUS parameter sets (it states optimal parameters such as number/volume of sessions and microbubble properties remain to be determined).

Duration of biological effect several days

Safety-related matter The paper reports that initial clinical trials support the safety of focused ultrasound (FUS)-mediated BBB opening, but also raises concerns about feasibility, patient burden, and the need to define optimal FUS parameters. It further states that safety, efficiency, and targeting of receptor-mediated transcytosis (RMT) and nanoparticle delivery remain poorly understood, particularly given AD heterogeneity and vascular comorbidities.

Brain Region

Visualization unavailable

Ultrasound Parameters

Focal Characteristics Focal depth: None; Focal length: None; Aperture size: None

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