Oleic-Acid-Derived Nonionic Amphiphiles as Nanoscale Drug Delivery Vehicles

Background/Objectives: The rational design of amphiphilic molecules that form stable nanostructures in aqueous media has attracted considerable attention for biomedical and drug-delivery applications. In this study, we designed and synthesized oleic-acid-based non-ionic amphiphiles incorporating different hydrophobic chains (alkyl/fluoroalkyl) and hydrophilic units such as polyethylene glycol (PEG) and lactose azide. Methods: The aggregation behavior and size distribution of the amphiphiles were investigated using dynamic light scattering (DLS), while the morphology of the self-assembled nanostructures was confirmed by transmission electron microscopy (TEM). The critical aggregation concentration (CAC) was determined using Nile red as a fluorescent probe. Nile red, nimodipine, and curcumin were used as hydrophobic cargo to assess amphiphile transport potential, while L929 fibroblast cell lines were used for cytotoxicity tests. Using Novozym 435, stimuli-responsive guest release was investigated. Results: All amphiphiles self-assembled into well-defined nanoscale micellar structures in aqueous medium, as shown by DLS and TEM. CAC ranged from 10−4 to 10−5 M. Cytotoxicity assessments demonstrated that none of the amphiphiles exhibited measurable toxicity at concentrations up to 0.5 mg/mL, affirming their biocompatibility. Alkylated amphiphiles displayed superior encapsulation efficiency for hydrophobic dye and drugs. The fluorescence intensity dropped 100% within 66 h in enzyme-triggered cargo release experiments, indicating regulated cargo release. Conclusions: Collectively, these findings demonstrate the robust encapsulation capacity and stimuli-responsive release behavior of these amphiphilic nanoarchitectures, establishing them as promising platforms for the development of advanced nanocarriers in biomedical applications.