Laboratory investigations for the morphologic, pharmacokinetic, and anti-retroviral properties of indinavir nanoparticles in human nomocyte-derived macrophages

被引:68
作者
Dou, Huanyu
Morehead, Justin
Destache, Christopher J.
Kingsley, Jeffrey D.
Shlyakhtenko, Lyudmila
Zhou, You
Chaubal, Mahesh
Werling, Jane
Kipp, James
Rabinow, Barrett E.
Gendelman, Howard E.
机构
[1] Univ Nebraska, Med Ctr, Dept Pharmacol & Expt Neurosci, Omaha, NE 68198 USA
[2] Univ Nebraska, Med Ctr, Ctr Neurovirol & Neurodegenerat Disorders, Omaha, NE 68198 USA
[3] Univ Nebraska, Med Ctr, Dept Internal Med, Omaha, NE 68198 USA
[4] Univ Nebraska, Med Ctr, Dept Pediat, Omaha, NE 68198 USA
[5] Univ Nebraska, Med Ctr, Dept Pharmaceut Sci, Omaha, NE 68198 USA
[6] Univ Nebraska, Dept Vet & Biomed Sci, Lincoln, NE 68588 USA
[7] Creighton Univ, Sch Pharm & Hlth Profess, Omaha, NE 68178 USA
[8] Baxter Healthcare Corp, Round Lake, IL 60073 USA
关键词
macrophages; nanoparticles; anti-retroviral efficacy; human immunodeficiency virus; indinavir;
D O I
10.1016/j.virol.2006.08.012
中图分类号
Q93 [微生物学];
学科分类号
071005 ; 100705 ;
摘要
The effectiveness of anti-retroviral therapies (ART) depends on its ultimate ability to clear reservoirs of continuous human immunodeficiency virus (HIV) infection. We reasoned that a principal vehicle for viral dissemination, the mononuclear phagocytes could also serve as an ART transporter and as such improve therapeutic indices. A nanoparticle-indinavir (NP-IDV) formulation was made and taken up into and released from vacuoles of human monocyte-derived macrophages (MDM). Following a single NP-IDV dose, drug levels within and outside MDM remained constant for 6 days without cytotoxicity. Administration of NP-IDV when compared to equal drug levels of free soluble IDV significantly blocked induction of multinucleated giant cells, production of reverse transcriptase activity in culture fluids and cell-associated HIV-1p24 antigens after HIV-1 infection. These data provide "proof of concept" for the use of macrophage-based NP delivery systems for human HIV-1 infections. (c) 2006 Elsevier Inc. All rights reserved.
引用
收藏
页码:148 / 158
页数:11
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