Design and physicochemical characterization of Glycerol-based dendritic nanocarriers for micellar delivery of hydrophobic drugs

Abstract

In this study, we report the design, synthesis, and physicochemical evaluation of four new non-ionic dendritic amphiphiles derived from glycerol-based dendrons incorporating biodegradable amide linkers as pH-sensitive moieties. These amphiphiles were synthesized through a modular approach, employing a polyglycerol core and hydrophobic alkyl chains of varying lengths introduced via amide bond formation. Structures were confirmed by using FTIR, ¹HNMR, and ¹³C NMR spectroscopy data. Owing to their amphiphilic nature, the molecules spontaneously assemble in aqueous media to form well-defined, stable micellar structures, as confirmed by surface tension analysis and dynamic light scattering (DLS). To evaluate their drug delivery potential, pyrene was used as a model hydrophobic guest molecule. Among the synthesised amphiphiles, the C₁₂-G₁ dendron demonstrated optimal encapsulation efficiency and was used for a release profile study. Drug release studies conducted under neutral (pH 7.0) and acidic (pH 5.3) conditions revealed a sustained release behaviour over 24 hours, with a significantly enhanced release under acidic conditions. Comparative analysis with previously developed ester-linked analogs revealed that amide-linked systems exhibit lower critical micelle concentrations (CMC), enhanced stability, and pH responsiveness. This work highlights the potential of amide linkers as a promising carrier for next-generation nanocarriers for hydrophobic drug delivery in biomedical applications.