Indole derivatives in smart polymeric formulations for targeted management of neurodegenerative disorders

Abstract

Indole derivatives represent a privileged scaffold with multi-target neuroprotective properties (antioxidant, anti-aggregatory, cholinesterase inhibition) but are often limited by poor aqueous solubility, metabolic instability, and restricted brain delivery. In this study, a focused series of indole derivatives was synthesized and characterized. Lead compounds were encapsulated into smart polymeric carriers — (i) ligand-functionalized PEG-PLA nanoparticles for receptor-mediated brain targeting, (ii) disulfide-linked redox-sensitive polymeric micelles for intracellular triggered release, and (iii) thiolated-chitosan intranasal nanogels for nose-to-brain delivery. Formulations were prepared by nanoprecipitation, emulsion–solvent evaporation, and ionotropic gelation respectively, and comprehensively evaluated for particle size, zeta potential, drug loading, encapsulation efficiency, in-vitro release under physiological and stimulus conditions, cytotoxicity, BBB permeation (hCMEC/D3 monolayer and transwell co-culture), and ex vivo brain uptake. Representative indole lead ITD-7 showed high encapsulation (EE 78–86%) and sustained release over 72 h with accelerated release under reductive (10 mM GSH) or acidic (pH 5.5) conditions. Targeted PEG-PLA NPs exhibited ~3.6-fold higher transendothelial transport compared to free ITD-7 and improved neuronal protection in Aβ-challenged SH-SY5Y cells. Thiolated-chitosan nanogels delivered therapeutically relevant drug levels to olfactory bulb tissue in ex vivo rat nasal perfusion studies. These results demonstrate that combining rational indole chemistry with stimulus-responsive, targeted polymeric systems yields promising platforms for targeted management of neurodegenerative disorders