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 (R) 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 (similar to 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. (C) 2011 Elsevier B.V. All rights reserved.