Surface-modified dendrimer nanoconjugate for targeting delivery of rifampicin

Abstract

Objective: The study aimed to formulate and evaluate the efficiency of surface-modified Polyamidoamine dendrimer (PAMAM) as a targeted nanocarrier for the antimycobacterial agent rifampicin. Methods: The periphery of dendrimer was modified with mannose using α-D-mannopyranosylphenyl isothiocyanate and characterized using analytical techniques i.e., infrared spectroscopy (FTIR) and nuclear magnetic resonance spectroscopy (NMR). Then, rifampicin was encapsulated into mannosylated dendrimers and evaluated for size, shape, encapsulation efficiency (EE%), drug-dendrimer interaction, and drug release. The toxicity of the nanoconjugates were assessed towards macrophages using the MTT technique. The study investigated the internalization of dendrimer nanoparticles into macrophages to assess the impact of mannose conjugation. Dendrimers were fluorescently labelled and the internalization was quantified using a fluorescence spectroscopy and flow cytometer methods. Results: Mannosylated dendrimers with different mannose densities were successfully developed. The nanoparticles were within the nanoscopic scale. The dendrimers appeared spheroidal under scanning electron microscopy (SEM), and thermal analysis confirmed the conjugation of rifampicin into the dendrimers. The nanoparticles exhibited a good EE% for rifampicin at 10.34 % w/w. After surface mannosylation, the EE% further increased, ranging from 43.43 % to 57.91 % w/w. Mannose-functionalized dendrimers prolonged rifampicin release in physiological pH, while a rapid release in pH 4.5 medium was noticed. The cytotoxicity of the dendrimers in RAW macrophages was considerably reduced after mannose functionalization. In vitro studies indicated that mannose significantly increased the macrophage uptake of nanoconjugates, likely via lectin receptor-mediated endocytosis. Conclusion: Overall results suggested mannosylated dendrimers as an effective targeted pulmonary delivery system for rifampicin with negligible cytotoxicity.