title: Anti-HIV efficacy and biodistribution of nucleoside reverse transcriptase inhibitors delivered as squalenoylated prodrug nanoassemblies.
abstract: Due to their hydrophilic nature, most nucleoside reverse transcriptase inhibitors (NRTIs) display a variable bioavailability after oral administration and a poor control over their biodistribution, thus hampering their access to HIV sanctuaries. The limited cellular uptake and activation in the triphosphate form of NRTIs further restrict their efficacy and favour the emergence of viral resistance. We have shown that the conjugation of squalene (sq) to the nucleoside analogues dideoxycytidine (ddC) and didanosine (ddI) leads to amphiphilic prodrugs (ddC-sq and ddI-sq) that spontaneously self-organize in water as stable nanoassemblies of 100-300 nm. These nanoassemblies can also be formulated with polyethylene glycol coupled to either cholesterol (Chol-PEG) or squalene (sq-PEG). When incubated with peripheral blood mononuclear cells (PBMCs) in vitro infected with HIV, the NRTI-sq prodrugs enhanced the antiviral efficacy of the parent NRTIs, with a 2- to 3-fold decrease of the 50% effective doses and a nearly 2-fold increase of the selectivity index. This was also the case with HIV-1 strains resistant to ddC and/or ddI. The enhanced antiviral activity of ddI-sq was correlated with an up to 5-fold increase in the intracellular concentration of the corresponding pharmacologically active metabolite ddA-TP. The ddI-sq prodrug was further investigated in vivo by the oral route, the preferred route of administration of NRTIs. Pharmacokinetics studies performed on rats showed that the prodrug maintained low amounts of free ddI in the plasma. Administration of (3)H-ddI-sq led to radioactivity levels higher in the plasma and relevant organs in HIV infection as compared to administration of free (3)H-ddI. Taken together, these results show the potential of the squalenoylated prodrugs of NRTIs to enhance their absorption and improve their biodistribution, but also to enhance their intracellular delivery and antiviral efficacy towards HIV-infected cells.
authors.affiliation: Institut Galien Paris-Sud, UMR 8612, Université Paris-Sud, Châtenay-Malabry, France.
authors.forename: Hervé
authors.initials: H
authors.lastname: Hillaireau
authors.forename: Nathalie
authors.initials: N
authors.lastname: Dereuddre-Bosquet
authors.forename: Rym
authors.initials: R
authors.lastname: Skanji
authors.forename: Fawzia
authors.initials: F
authors.lastname: Bekkara-Aounallah
authors.forename: Joachim
authors.initials: J
authors.lastname: Caron
authors.forename: Sinda
authors.initials: S
authors.lastname: Lepêtre
authors.forename: Sébastien
authors.initials: S
authors.lastname: Argote
authors.forename: Laurent
authors.initials: L
authors.lastname: Bauduin
authors.forename: Rahima
authors.initials: R
authors.lastname: Yousfi
authors.forename: Christine
authors.initials: C
authors.lastname: Rogez-Kreuz
authors.forename: Didier
authors.initials: D
authors.lastname: Desmaële
authors.forename: Bernard
authors.initials: B
authors.lastname: Rousseau
authors.forename: Ruxandra
authors.initials: R
authors.lastname: Gref
authors.forename: Karine
authors.initials: K
authors.lastname: Andrieux
authors.forename: Pascal
authors.initials: P
authors.lastname: Clayette
authors.forename: Patrick
authors.initials: P
authors.lastname: Couvreur
mesh_terms: D000255:Adenosine Triphosphate / Q000494:pharmacology; D000818:Animals; D019380:Anti-HIV Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D016049:Didanosine / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D024882:Drug Resistance, Viral / Q000187:drug effects; D008027:Light; D053758:Nanoparticles / Q000737:chemistry* / Q000648:ultrastructure; D009705:Nucleosides / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D010316:Particle Size; D011355:Prodrugs / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D018894:Reverse Transcriptase Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D012542:Scattering, Radiation; D013185:Squalene / Q000737:chemistry*; D014018:Tissue Distribution / Q000187:drug effects; D016896:Treatment Outcome; D014316:Tritium; D016047:Zalcitabine / Q000737:chemistry / Q000494:pharmacology
chemical_list: D019380:Anti-HIV Agents; D009705:Nucleosides; D011355:Prodrugs; D018894:Reverse Transcriptase Inhibitors; D014316:Tritium; D016047:Zalcitabine; D013185:Squalene; D000255:Adenosine Triphosphate; D016049:Didanosine