Designing multitarget ligands for neurodegenerative diseases with improved permeability trough PLGA nanoencapsulation

Multitarget ligands (MTLs) have emerged as an interesting alternative for addressing complex multifactorial pathologies such as neurodegenerative diseases. However, a common challenge associated with these compounds is often their high molecular weight and low solubility, which becomes a hurdle when trying to permeate over the blood-brain barrier (BBB). In this study, we have designed two new MTLs that modulate three pharmacological targets simultaneously (tau, beta-amyloid and TAR DNA-binding protein 43). To enhance their brain penetration, we have formulated organic polymeric nanoparticles using poly(lactic-co-glycolic acid). The characterization of the formulations, evaluation of their permeability through an in vitro BBB model, and assessment of their activity on disease-representative cellular models, such as Alzheimer’s disease and amyotrophic lateral sclerosis, have been conducted. The results demonstrate the potential of the new MTLs and their nanoparticle encapsulation for the treatment of neurodegenerative diseases. [Display omitted] •MTLs able to modulate several tau and TDP-43 kinases plus Aβ pathology may be effective drugs for AD and/or ALS.•Main limitation of MTLs is the poor CNS permeability because their high molecular weight and large polar surface areas.•PLGA nanoparticles represent a useful methodology to improve the brain penetration of MTLs.•PLGA nanoparticles loaded with MTLs demonstrate a superior neuroprotective effect compared to MTLs alone.