Design of Aquasome-Based Systems for Brain-Targeted Delivery of DDL-920

Alzheimer’s disease (AD) remains one of the most difficult neurological disorders to manage, largely because existing treatments provide only modest benefit and most drug candidates fail to cross the blood–brain barrier (BBB) in effective amounts. DDL-920, a small molecule with neuroprotective activity, has shown encouraging preclinical effects, including a 45% improvement in spatial memory and a 38% reduction in amyloid plaque burden in transgenic mouse models. However, its clinical application has been limited by very low aqueous solubility (<0.5 µg/mL), poor oral bioavailability (~12%), and minimal brain penetration (brain/plasma ratio <0.08). To overcome these challenges, aquasome-based nanocarriers were developed as delivery systems for DDL-920. The optimized formulation demonstrated favorable physicochemical characteristics, with a particle size of 152.3 ± 6.4 nm, zeta potential of –21.6 ± 2.3 mV, and an encapsulation efficiency of 82.4 ± 3.5%. In vitro release experiments confirmed a sustained drug profile, with 74% release at 48 h, along with a 12-fold improvement in solubility compared to the free drug. BBB transport studies in hCMEC/D3 cells indicated a 4.3-fold higher permeability for the aquasomes, and in vivo testing revealed greater brain accumulation (2.6 ± 0.4 µg/g vs. 0.5 ± 0.1 µg/g). Behavioral evaluations in AD mice further showed superior memory recovery, with 65% improvement versus 28% for the free drug. Overall, these findings support aquasome technology as a promising platform for enhancing the therapeutic potential of DDL-920 in Alzheimer’s disease.