Long-acting three-drug combination anti-HIV nanoparticles enhance drug exposure in primate plasma and cells within lymph nodes and blood

Freeling, Jennifer; Koehn, Josefin; Shu, Cuiling; Sun, Jianguo; Ho, Rodney J. Y.

doi:10.1097/qad.0000000000000421

Cited by 60 publications

(54 citation statements)

References 18 publications

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“…Freeling et al produced solid lipid nanoparticles containing boosted lopinavir (L/r) and TFV. Using macaque model, the investigators demonstrated enhanced penetration of the ARV drugs into lymph nodes compared to that of free drugs (10,27). Other investigators have used wet-milled technique to develop FTC crystals that boosted protease inhibitor efficacy in humanized mice when linked with folic acid (28,29).…”

Section: Discussionmentioning

confidence: 99%

“…In ARV encapsulations into a nanoparticle formulation, drugs are released from the nanoparticles over an extended period, allowing for once-monthly or longer treatment modalities (7)(8)(9). However, the encapsulation of water-soluble ARV drugs, namely, NRTIs such as FTC, has been difficult, and the encapsulation efficiency has been quite low (10). Our laboratory has been working on solving this problem.…”

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confidence: 99%

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An Enhanced Emtricitabine-Loaded Long-Acting Nanoformulation for Prevention or Treatment of HIV Infection

Mandal

Belshan

Holec

et al. 2017

Antimicrob Agents Chemother

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Among various FDA-approved combination antiretroviral drugs (cARVs), emtricitabine (FTC) has been a very effective nucleoside reverse transcriptase inhibitor. Thus far, FTC is the only deoxycytidine nucleoside analog. However, a major drawback of FTC is its large volume distribution (averaging 1.4 liters/kg) and short plasma half-life (8 to 10 h), necessitating a high daily dosage. Thus, we propose an innovative fabrication method of loading FTC in poly(lactic-co-glycolic acid) polymeric nanoparticles (FTC-NPs), potentially overcoming these drawbacks. Our nanoformulation demonstrated enhanced FTC loading (size of Ͻ200 nm and surface charge of Ϫ23 mV) and no to low cytotoxicity with improved biocompatibility compared to those with FTC solution. An ex vivo endosomal release assay illustrated that NP entrapment prolongs FTC release over a month. Intracellular retention studies demonstrate sustained FTC retention over time, with approximately 8% (24 h) to 68% (96 h) release with a mean retention of ϳ0.74 g of FTC/10 5 cells after 4 days. An in vitro HIV-1 inhibition study demonstrated that FTC-NP treatment results in a 50% inhibitory concentration (IC 50 ) ϳ43 times lower in TZM-bl cells (0.00043 g/ml) and ϳ3.7 times lower (0.009 g/ml) in peripheral blood mononuclear cells (PBMCs) than with FTC solution (TZM-bl cells, 0.01861, and PBMCs, 0.033 g/ml). Further, on primary PBMCs, FTC-NPs also illustrate an HIV-1 infection blocking efficacy comparable to that of FTC solution. All the above-described studies substantiate that FTC nanoformulation prolongs intracellular FTC concentration and inhibition of HIV infection. Therefore, FTC-NPs potentially could be a long-acting, stable formulation to ensure once-biweekly dosing to prevent or treat HIV infection.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

An Enhanced Emtricitabine-Loaded Long-Acting Nanoformulation for Prevention or Treatment of HIV Infection

Mandal

Belshan

Holec

et al. 2017

Antimicrob Agents Chemother

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“…The results of this study suggested that Tef disoproxil fumarate-NF acted as an LA drug via sustained release of Tef to show coitus-independent HIV-1 vaginal protection modality. 24 Freeling et al 25 developed an NF containing three LA anti-HIV drugs (lopinavir, ritonavir, and Tef) loaded in a lipid nanoparticle for longer exposure in primate plasma cells within lymph nodes (persistent HIV reservoirs) and blood to cure HIV infection. This developed NF showed 50-fold higher intracellular drug concentration in lymph in comparison to free drug administration.…”

Section: Kaushik Et Almentioning

confidence: 99%

“…Thus, the presented NF can be used as oral therapy for HIV at the periphery level. 25 Roy et al 26 developed an NF (140 nm) to eradicate HIV infection in the gut-associated lymphoid tissue (GALT), a reservoir of early HIV infection and host-pathogen interaction. The complex physiology of GALT resisted delivery of conventional anti-HIV drugs.…”

Section: Kaushik Et Almentioning

confidence: 99%

Advancements in nano-enabled therapeutics for neuroHIV management

Jayant¹,

Nair²

2016

IJN

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This viewpoint is a global call to promote fundamental and applied research aiming toward designing smart nanocarriers of desired properties, novel noninvasive strategies to open the blood-brain barrier (BBB), delivery/release of single/multiple therapeutic agents across the BBB to eradicate neurohuman immunodeficiency virus (HIV), strategies for on-demand site-specific release of antiretroviral therapy, developing novel nanoformulations capable to recognize and eradicate latently infected HIV reservoirs, and developing novel smart analytical diagnostic tools to detect and monitor HIV infection. Thus, investigation of novel nanoformulations, methodologies for site-specific delivery/release, analytical methods, and diagnostic tools would be of high significance to eradicate and monitor neuroacquired immunodeficiency syndrome. Overall, these developments will certainly help to develop personalized nanomedicines to cure HIV and to develop smart HIV-monitoring analytical systems for disease management.

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“…The availability of a simple, sensitive, selective, efficient, and validated assay has enabled reliable quality control in the production of longacting anti-HIV combination drug nanoparticles containing LPV, RTV, and TFV and the in vivo pharmacokinetic analysis of the nanoparticles and their distribution to the lymphoid tissue and blood mononuclear cells (16).…”

mentioning

confidence: 99%

A Simple, Efficient, and Sensitive Method for Simultaneous Detection of Anti-HIV Drugs Atazanavir, Ritonavir, and Tenofovir by Use of Liquid Chromatography-Tandem Mass Spectrometry

Koehn

Ding

Freeling

et al. 2015

Antimicrob Agents Chemother

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In the treatment of HIV infection, a combination of anti-HIV drugs is commonly used in highly active antiretroviral therapy (HAART). One such combination recommended for clinical therapy consists of the two HIV protease inhibitors atazanavir and ritonavir and the HIV nucleotide reverse transcriptase inhibitor tenofovir. The detection of plasma and cell drug concentrations provides an assessment of actual drug exposure and patient compliance. We thus developed a simple, efficient, and sensitive method to simultaneously extract and detect these three drugs in plasma and peripheral blood mononuclear cells. The use of a liquid-liquid extraction followed by protein precipitation provided a simple process, yielding a high recovery rate for all three drugs in plasma (>92%) and in cells (>86%). The liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay was able to detect 0.01, 0.25, and 2.5 pg (2, 50, and 500 pg/ml, respectively) in 5 l for atazanavir, ritonavir, and tenofovir, respectively. Validation of the method exhibited high precision and accuracy. This method was subsequently applied to a primate study to determine the concentrations of all three drugs in both plasma and cell samples. This validated method can be useful for an evaluation of drug concentrations in biological samples in an efficient and sensitive manner. Since the introduction of highly active antiretroviral therapy (HAART) in the 1990s, the outcome in terms of life expectancy for people suffering from human immunodeficiency virus (HIV) has greatly improved due to the plasma virus load reduction to below-detectable levels (1, 2). ART treatment usually includes two or three anti-HIV drugs from different drug classes targeting different viral proteins in order to increase efficacy and lower the risk of the virus developing resistance to the treatment. A common drug combination is a nucleoside or nucleotide reverse transcriptase inhibitor (NRTI or NtRTI, respectively) with a nonnucleoside reverse transcriptase inhibitor (NNRTI) or with one or more protease inhibitors (PIs) (3).One of the first-line therapies recommended for ART-naive people is the combination of atazanavir (ATZ), ritonavir (RTV), and tenofovir (TFV) (3). ATZ is a commonly used PI that exhibits 10-to 100-fold higher antiviral potency than that of other PIs, including nelfinavir or indinavir, and demonstrates a lower rate of viral drug resistance (4-9). ATZ is typically used in combination with RTV, another PI, which inhibits the cytochrome P450 3A isoenzyme (CYP3A) metabolism of ATZ, thereby boosting ATZ exposure. RTV has also been shown to inhibit drug efflux transport by P-glycoprotein (PgP) and therefore might enhance the cellular retention of other PIs (10). TFV is a nucleotide reverse transcriptase inhibitor (NtRTI) clinically administered as tenofovir disoproxil fumarate (TDF), an oral prodrug that increases absorption and is readily hydrolyzed to the TFV active form (11). While a number of bioanalytical assays have been developed for the three drugs, they are often time...

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Long-acting three-drug combination anti-HIV nanoparticles enhance drug exposure in primate plasma and cells within lymph nodes and blood

Cited by 60 publications

References 18 publications

An Enhanced Emtricitabine-Loaded Long-Acting Nanoformulation for Prevention or Treatment of HIV Infection

An Enhanced Emtricitabine-Loaded Long-Acting Nanoformulation for Prevention or Treatment of HIV Infection

Advancements in nano-enabled therapeutics for neuroHIV management

A Simple, Efficient, and Sensitive Method for Simultaneous Detection of Anti-HIV Drugs Atazanavir, Ritonavir, and Tenofovir by Use of Liquid Chromatography-Tandem Mass Spectrometry

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