title: Optimization of lipid-indinavir complexes for localization in lymphoid tissues of HIV-infected macaques.
abstract: In HIV-infected persons on highly active antiretroviral therapy, residual virus is found in lymphoid tissues. Indinavir concentrations in lymph node mononuclear cells of patients on highly active antiretroviral therapy were approximately 25% to 35% of those in blood mononuclear cells, suggesting that drug insufficiency contributes to residual virus in lymphoid tissues. Therefore, we developed novel lipid-indinavir nanoparticles targeted to lymphoid tissues. Given subcutaneously, these nanoparticles provided indinavir concentrations 250% to 2270% higher than plasma indinavir concentrations in both peripheral and visceral lymph nodes. Improved indinavir delivery was reflected in reduced viral RNA and CD4(+) T-cell rebound. This study optimized lipid nanoparticle formulation with respect to indinavir in lymphoid tissues of HIV-infected macaques. Regardless of lipid characteristic tested (charge, fluidity, and steric modification), indinavir binds completely to lipid at pH 7.4 but is reversed at pH 5.5 or lower. Compared with previous formulations, nanoparticles composed of disteroyl phosphatidylcholine and methyl polyethylene glycol-disteroyl phosphatidylethanolamine (DSPC:mPEG-DSPE) provided 6-fold higher indinavir levels in lymph nodes and enhanced drug exposure in blood. Enhanced anti-HIV activity paralleled improved intracellular drug accumulation. Collectively, these data suggest that indinavir nanoparticles composed of DSPC:mPEG-DSPE provided the most effective lymphoid delivery and could maximally suppress the virus in lymphoid tissues.
authors.affiliation: Department of Pharmaceutics, University of Washington, Seattle, WA 98195, USA.
authors.forename: Loren
authors.initials: L
authors.lastname: Kinman
authors.forename: Tot
authors.initials: T
authors.lastname: Bui
authors.forename: Kay
authors.initials: K
authors.lastname: Larsen
authors.forename: Che-Chung
authors.initials: CC
authors.lastname: Tsai
authors.forename: David
authors.initials: D
authors.lastname: Anderson
authors.forename: William R
authors.initials: WR
authors.lastname: Morton
authors.forename: Shiu-Lok
authors.initials: SL
authors.lastname: Hu
authors.forename: Rodney J Y
authors.initials: RJ
authors.lastname: Ho
mesh_terms: D000818:Animals; D019380:Anti-HIV Agents / Q000008:administration & dosage* / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology; D018791:CD4 Lymphocyte Count; D002460:Cell Line; D004195:Disease Models, Animal; D004337:Drug Carriers; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology; D015498:HIV-2; D006863:Hydrogen-Ion Concentration; D019469:Indinavir / Q000008:administration & dosage* / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology; D007279:Injections, Subcutaneous; D008055:Lipids / Q000008:administration & dosage / Q000493:pharmacokinetics; D008198:Lymph Nodes / Q000737:chemistry; D008221:Lymphoid Tissue / Q000737:chemistry*; D008254:Macaca nemestrina; D049329:Nanostructures / Q000737:chemistry; D010713:Phosphatidylcholines / Q000493:pharmacokinetics; D012367:RNA, Viral / Q000097:blood; D014018:Tissue Distribution
chemical_list: D019380:Anti-HIV Agents; D004337:Drug Carriers; D008055:Lipids; D010713:Phosphatidylcholines; D012367:RNA, Viral; D019469:Indinavir