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-phasehigh-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 M 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. ( IntroductionDespite the significant impact of antiretroviral therapy (ART), the worldwide human immunodeficiency virus type 1 (HIV-1) pandemic continues to grow. [1][2][3] An estimated 40 million people globally are virus infected, with the majority from the developing world. [4][5][6] Although ART has reduced disease morbidity and increased life expectancy, drug expenses, treatment failures, and dosing complexities limit global access. [7][8][9] Multiple daily dosing regimens and untoward secondary side effects diminish achievement of significant long-term HIV-1 suppression in infected people. [10][11][12] Additionally, continuous viral suppression requires maintenance of therapeutically effective drug concentrations. [13][14][15] Most significantly, elimination of viral reservoirs in the infected human host has not yet been achieved. 16,17 To address these challenges to effective antiretroviral delivery, we designed a novel bone marrow-derived macrophage (BMM) pharmacologic nanoparticle (NP) delivery system. This system could provide a strategy to achieve therapeutic efficacy, improve drug distribution to areas of active viral replication, and extend dosing intervals. Because of the small size of the NPs and their highly stable nature, NPs could be packaged within macrophages for subsequent systemic trafficking and sustained drug distribution. We reasoned that such a cell-based drug delivery system could reflect the patterns of viral replication and improve therapeutic outcomes.To test this idea, we loaded indinavir (IDV) nanosuspension into BMMs and administered intravenously into naive mice. Cell tissue distribution was tracked by single-photon emission computed tomography (SPECT) and T 2 * weighted magnetic resonance imaging (MRI) of radio-and superparamagnetic iron oxide (SPIO; Feridex)-labeled BMMs, and confirme...
Background Factors limiting the efficacy of conventional antiretroviral therapy for HIV-1 infection include treatment adherence, pharmacokinetics and penetration into viral sanctuaries. These affect the rate of viral mutation and drug resistance. In attempts to bypass such limitations, nanoparticles containing ritonavir, indinavir and efavirenz (described as nanoART) were manufactured to assess macrophage-based drug delivery. Methods NanoART were made by high-pressure homogenization of crystalline drug with various surfactants. Size, charge and shape of the nanoparticles were assessed. Monocyte-derived macrophage nanoART uptake, drug release, migration and cytotoxicity were determined. Drug levels were measured by reverse-phase high-performance liquid chromatography. Results Efficient monocyte-derived macrophage cytoplasmic vesicle uptake in less than 30 min based on size, charge and coating was observed. Antiretroviral drugs were released over 14 days and showed dose-dependent reduction in progeny virion production and HIV-1 p24 antigen. Cytotoxicities resulting from nanoART carriage were limited. Conclusion These results support the continued development of macrophage-mediated nanoART carriage for HIV-1 disease.
Antiretroviral therapy (ART) shows variable blood-brain barrier penetration. This may affect the development of neurological complications of HIV infection. In attempts to attenuate viral growth for the nervous system, cell-based nanoformulations were developed with the focus on improving drug pharmacokinetics. We reasoned that ART carriage could be facilitated within blood-borne macrophages traveling across the blood-brain barrier. To test this idea, an HIV-1 encephalitis (HIVE) rodent model was used where HIV-1-infected human monocyte-derived macrophages were stereotactically injected into the subcortex of severe combined immunodeficient mice. ART was prepared using indinavir (IDV) nanoparticles (NP, nanoART) loaded into murine bone marrow macrophages (BMM, IDV-NP-BMM) after ex vivo cultivation. IDV-NP-BMM was administered i.v. to mice resulting in continuous IDV release for 14 days. Rhodamine-labeled IDV-NP was readily observed in areas of HIVE and specifically in brain subregions with active astrogliosis, microgliosis, and neuronal loss. IDV-NP-BMM treatment led to robust IDV levels and reduced HIV-1 replication in HIVE brain regions. We conclude that nanoART targeting to diseased brain through macrophage carriage is possible and can be considered in developmental therapeutics for HIV-associated neurological disease.
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