Co delivery of HIV 1 entry inhibitor and nonnucleoside reverse transcriptase inhibitor shuttled by nanoparticles: cocktail therapeutic strategy for antiviral therapy
Objectives:Traditionally, the antiviral efficacy of classic cocktail therapy is significantly limited by the distinct pharmacokinetic profiles of partner therapeutics that lead to inconsistent in vivo biodistribution. Here we developed a new cocktail like drug delivery vehicle using biodegradable polymeric nanoparticles (NP) encapsulating nonnucleoside reverse transcriptase inhibitor (NNRTI) DAAN 14f (14f) surface conjugated with HIV 1 fusion inhibitor T1144, designated T1144 NP DAAN 14f (T1144 NP 14f) and aiming to achieve enhanced cellular uptake, improved antiviral activity and prolonged blood circulation time. Methods:T1144 NP 14f was prepared through the emulsion/solvent evaporation technique and a maleimide thiol coupling reaction. Particle size and morphology were determined by dynamic light scattering detection and transmission electron microscopy. Anti HIV 1 activity was assessed by HIV 1 Env mediated cell cell fusion and infection by laboratory adapted, primary, and resistant HIV 1 isolates, respectively. The in vitro release of 14f was investigated using the equilibrium dialysis method, and the pharmacokinetic study of T1144 NP 14f was performed on Sprague Dawley rats. Results:T1144 NP 14f displayed a spherical shape under transmission electron microscopy observation and had a size of 117 19 nm. T1144 NP 14f exhibited the strongest antiviral activity against a broad spectrum of HIV 1 strains, including NNRTI T1144 or T20 resistant isolates, respectively. Both in vitro release and in vivo pharmacokinetic profile showed that T1144 NP 14f exhibited a sustained controlled release behavior. Conclusion:Our results demonstrated that the combination of entry inhibitor with NNRTI encapsulated in nanoparticles (T1144 NP 14f) was highly effective in inhibiting HIV 1 infection. This new cocktail like drug delivery platform could serve as an effective anti HIV 1 regimen by taking advantage of the extrinsic and intrinsic antiviral activity of individual drugs.
AIDS