title: Co-delivery of HIV-1 entry inhibitor and nonnucleoside reverse transcriptase inhibitor shuttled by nanoparticles: cocktail therapeutic strategy for antiviral therapy.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: aKey Laboratory of Medical Molecular Virology of Ministries of Education and Health, Basic Medical College and Shanghai Public Health Clinical Center, Fudan University, Shanghai, ChinabLindsley F. Kimball Research Institute, New York Blood Center, New York, USAcBeijing Institute of Pharmacology and Toxicology, BeijingdShanghai Institute of Planned Parenthood Research, Shanghai, China.*Lu Lu and Shibo Jiang contributed equally to this work.
authors.forename: Wen
authors.initials: W
authors.lastname: Li
authors.forename: Fei
authors.initials: F
authors.lastname: Yu
authors.forename: Qian
authors.initials: Q
authors.lastname: Wang
authors.forename: Qianqian
authors.initials: Q
authors.lastname: Qi
authors.forename: Shan
authors.initials: S
authors.lastname: Su
authors.forename: Lan
authors.initials: L
authors.lastname: Xie
authors.forename: Lu
authors.initials: L
authors.lastname: Lu
authors.forename: Shibo
authors.initials: S
authors.lastname: Jiang
mesh_terms: D000818:Animals; D019380:Anti-HIV Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D063566:Biodegradable Plastics; D002460:Cell Line; D003692:Delayed-Action Preparations / Q000008:administration & dosage; D004337:Drug Carriers / Q000008:administration & dosage*; D000067493:Dynamic Light Scattering; D015497:HIV-1 / Q000187:drug effects / Q000502:physiology; D006801:Humans; D020128:Inhibitory Concentration 50; D008297:Male; D046529:Microscopy, Electron, Transmission; D053758:Nanoparticles / Q000008:administration & dosage* / Q000648:ultrastructure; D017207:Rats, Sprague-Dawley; D018894:Reverse Transcriptase Inhibitors; D016662:Virus Integration / Q000187:drug effects; D053586:Virus Internalization / Q000187:drug effects
chemical_list: D019380:Anti-HIV Agents; D063566:Biodegradable Plastics; D003692:Delayed-Action Preparations; D004337:Drug Carriers; D018894:Reverse Transcriptase Inhibitors