TY - JOUR
T1 - Development of a macrophage-based nanoparticle platform for antiretroviral drug delivery
AU - Dou, Huanyu
AU - Destache, Christopher J.
AU - Morehead, Justin R.
AU - Mosley, R Lee
AU - Boska, Michael D.
AU - Kingsley, Jeffrey
AU - Gorantla, Santhi
AU - Poluektova, Larisa Y
AU - Nelson, Jay A.
AU - Chaubal, Mahesh
AU - Werling, Jane
AU - Kipp, James
AU - Rabinow, Barrett E.
AU - Gendelman, Howard Eliot
PY - 2006/10/15
Y1 - 2006/10/15
N2 - Complex dosing regimens, costs, side effects, biodistribution limitations, and variable drug pharmacokinetic patterns have affected the long-term efficacy of antiretroviral medicines. To address these problems, a nanoparticle indinavir (NP-IDV) formulation packaged into carrier bone marrow-derived macrophages (BMMs) was developed. Drug distribution and disease outcomes were assessed in immune-competent and human immunodeficiency virus type 1 (HIV-1)-infected humanized immune-deficient mice, respectively. In the former, NP-IDV formulation contained within BMMs was adoptively transferred. After a single administration, single-photon emission computed tomography, histology, and reverse-phase-high-performance liquid chromatography (RP-HPLC) demonstrated robust lung, liver, and spleen BMMs and drug distribution. Tissue and sera IDV levels were greater than or equal to 50 μM for 2 weeks. NP-IDV-BMMs administered to HIV-1-challenged humanized mice revealed reduced numbers of virus-infected cells in plasma, lymph nodes, spleen, liver, and lung, as well as, CD4+ T-cell protection. We conclude that a single dose of NP-IDV, using BMMs as a carrier, is effective and warrants consideration for human testing.
AB - Complex dosing regimens, costs, side effects, biodistribution limitations, and variable drug pharmacokinetic patterns have affected the long-term efficacy of antiretroviral medicines. To address these problems, a nanoparticle indinavir (NP-IDV) formulation packaged into carrier bone marrow-derived macrophages (BMMs) was developed. Drug distribution and disease outcomes were assessed in immune-competent and human immunodeficiency virus type 1 (HIV-1)-infected humanized immune-deficient mice, respectively. In the former, NP-IDV formulation contained within BMMs was adoptively transferred. After a single administration, single-photon emission computed tomography, histology, and reverse-phase-high-performance liquid chromatography (RP-HPLC) demonstrated robust lung, liver, and spleen BMMs and drug distribution. Tissue and sera IDV levels were greater than or equal to 50 μM for 2 weeks. NP-IDV-BMMs administered to HIV-1-challenged humanized mice revealed reduced numbers of virus-infected cells in plasma, lymph nodes, spleen, liver, and lung, as well as, CD4+ T-cell protection. We conclude that a single dose of NP-IDV, using BMMs as a carrier, is effective and warrants consideration for human testing.
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U2 - 10.1182/blood-2006-03-012534
DO - 10.1182/blood-2006-03-012534
M3 - Article
C2 - 16809617
AN - SCOPUS:33750611615
SN - 0006-4971
VL - 108
SP - 2827
EP - 2835
JO - Blood
JF - Blood
IS - 8
ER -