Targeted delivery of indinavir to HIV-1 primary reservoirs with immunoliposomes.
The tissue distribution of indinavir, free or incorporated into sterically stabilized anti-HLA-DR immunoliposomes, has been evaluated after a single subcutaneous injection to C3H mice. Administration of free indinavir resulted in low drug levels in lymphoid organs. In contrast, sterically stabilized anti-HLA-DR immunoliposomes were very efficient in delivering high concentrations of indinavir to lymphoid tissues for at least 15 days post-injection increasing by up to 126 times the drug accumulation in lymph nodes. The efficacy of free and immunoliposomal indinavir has been evaluated in vitro. Results showed that immunoliposomal indinavir was as efficient as the free agent to inhibit HIV-1 replication in cultured cells. The toxicity and immunogenicity of repeated administrations of liposomal formulations have also been investigated in rodents. No significant differences in the levels of hepatic enzymes of mice treated with free or liposomal indinavir were observed when compared to baseline and control untreated mice. Furthermore, histopathological studies revealed no significant damage to liver and spleen when compared to the control group. Liposomes bearing Fab' fragments were 2.3-fold less immunogenic than liposomes bearing the entire IgG. Incorporation of antiviral agents into sterically stabilized immunoliposomes could represent a novel therapeutic strategy to target specifically HIV reservoirs and treat more efficiently this retroviral infection.
Gagné
Jean-François
JF
Centre de Recherche en Infectiologie, Centre Hospitalier Universitaire de Québec, Pavillon CHUL, 2705 Blvd Laurier, Université Laval, Quebec, QC, Canada.
Désormeaux
André
A
Perron
Sylvie
S
Tremblay
Michel J
MJ
Bergeron
Michel G
MG
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D000911:Antibodies, Monoclonal; D001219:Aspartate Aminotransferases / Q000097:blood; D015496:CD4-Positive T-Lymphocytes; D002460:Cell Line; D016503:Drug Delivery Systems; D017320:HIV Protease Inhibitors / Q000008:administration & dosage* / Q000493:pharmacokinetics; D015497:HIV-1 / Q000187:drug effects*; D006684:HLA-DR Antigens / Q000276:immunology*; D019469:Indinavir / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000633:toxicity; D007770:L-Lactate Dehydrogenase / Q000097:blood; D008081:Liposomes; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution
D000911:Antibodies, Monoclonal; D017320:HIV Protease Inhibitors; D006684:HLA-DR Antigens; D008081:Liposomes; D019469:Indinavir; D007770:L-Lactate Dehydrogenase; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase