pH-responsive nanoparticles releasing tenofovir intended for the prevention of HIV transmission

This study is designed to test the hypothesis that tenofovir (TNF) or tenofovir disoproxil fumarate (TDF) loaded nanoparticles (NPs) prepared with a blend of poly(lactic-co-glycolic acid) (PLGA) and methacrylic acid copolymer (Eudragit® S-100, or S-100) are noncytotoxic and exhibit significant pH-responsive release of anti-HIV microbicides in the presence of human semen fluid simulant (SFS). After NPs preparation by emulsification diffusion, their size, encapsulation efficiency (EE%), drug release profile, morphology, and cytotoxicity are characterized by dynamic light scattering, spectrophotometry, transmission electron microscopy, and cellular viability assay/transepithelial electrical resistance measurement, respectively. Cellular uptake was elucidated by fluorescence spectroscopy and confocal microscopy. The NPs have an average size of 250 nm, maximal EE% of 16.1% and 37.2% for TNF and TDF, respectively. There is a 4-fold increase in the drug release rate from the 75% S-100 blend in the presence of SFS over 72 h. At a concentration up to 10 mg/ml, the PLGA/S-100 NPs are noncytotoxic for 48 h to vaginal endocervical/epithelial cells and Lactobacillus crispatus. The particle uptake (∼50% in 24 h) by these vaginal cell lines mostly occurred through caveolin-mediated pathway. These data suggest the promise of using PLGA/S-100 NPs as an alternative controlled drug delivery system in intravaginal delivery of an anti-HIV/AIDS microbicide.

(A) Confocal microscopy showing coumarin-6 loaded pH-responsive NPs uptaken by vaginal epithelial cells after 4 h incubation. (B) In vitro release profile at pH = 4.2 (solid line) and pH = 7.6 (dash line) of model microbicide (tenofovir) from pH responsive NPs (n = 3).Figure optionsDownload as PowerPoint slide