Fabrication of Redox and Hydrolase-Responsive Nonionic Bola-Amphiphiles as Efficient Nanotransport Systems for Drug Delivery Applications

A series of disulfide- and ester-based nonionic bola-amphiphiles have been synthesized around a central lipophilic core constituted by conjugating suberic acid/3,3′-dithiodipropionic acid with dipropargyl isophthalate via esterification reaction. The azide derivative of monomethoxy polyethylene glycol (mPEG) moieties was covalently linked to the central core via click chemistry to confer hydrophilicity. The resulting amphiphiles have the tendency to undergo aggregation in the aqueous medium, forming nanosized architectures as evidenced by dynamic light scattering (DLS) measurements and high-resolution transmission electron microscopic (HRTEM) study. The inner hydrophobic core of these aggregates facilitates the encapsulation of model hydrophobic guests, i.e., Nile red, a hydrophobic dye, and nimodipine, a calcium channel-blocking drug. The presence of disulfide and ester linkages enables the amphiphiles to exhibit stimuli-responsive behavior toward glutathione and an enzyme (hydrolase), thus allowing the systematic release of the cargo under specific medical conditions. From the biomedical perspective, the cytotoxicity and cellular uptake study of synthesized amphiphiles was performed using HeLa cells. The obtained experimental data suggest that the synthesized bola-amphiphiles have potential applications as stimuli-responsive delivery vehicles.