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

Mandal, Subhra; Belshan, Michael; Holec, Ashley D.; Zhou, You; Destache, Christopher J.

doi:10.1128/aac.01475-16

Cited by 39 publications

(52 citation statements)

References 34 publications

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“…The potential of PEG-400 has been studied extensively in solubility enhancement of various drugs [9][10][11][12][13][14][15][16][17][18]. Several formulation approaches including "3D printed controlled release tablets [4], film coated tablets [19], rapidly disintegrating vaginal tablets [20], immediate release tablets [21], vaginal gels [22], liposomal gels [23], microparticulate drug delivery system [24], nanosuspensions [25,26] and polymeric nanoparticles [5,27,28]" were reported to improve antiviral therapy and pharmacokinetic profile of ECT. The equilibrium solubility of ECT in water was found as 112 mg mL −1 at "T = 298.2 K" [1].…”

Section: Introductionmentioning

confidence: 99%

Solubility, Hansen Solubility Parameters and Thermodynamic Behavior of Emtricitabine in Various (Polyethylene Glycol-400 + Water) Mixtures: Computational Modeling and Thermodynamics

2020

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This study was aimed to find out the solubility, thermodynamic behavior, Hansen solubility parameters and molecular interactions of an antiviral drug emtricitabine (ECT) in various “[polyethylene glycol-400 (PEG-400) + water]” mixtures. The solubility of ECT in mole fraction was determined at “T = 298.2 to 318.2 K” and “p = 0.1 MPa” using an isothermal method. The experimental solubilities of ECT in mole fraction were validated and correlated using various computational models which includes “Van’t Hoff, Apelblat, Yalkowsky-Roseman, Jouyban-Acree and Jouyban-Acree-Van’t Hoff models”. All the models performed well in terms of model correlation. The solubility of ECT was increased with the raise in temperature in all “PEG-400 + water” mixtures studied. The highest and lowest solubility values of ECT were found in pure PEG-400 (1.45 × 10−1) at “T = 318.2 K” and pure water (7.95 × 10−3) at “T = 298.2 K”, respectively. The quantitative values of activity coefficients indicated higher interactions at molecular level in ECT and PEG-400 combination compared with ECT and water combination. “Apparent thermodynamic analysis” showed an “endothermic and entropy-driven dissolution” of ECT in all “PEG-400 + water” combinations studied. The solvation nature of ECT was found an “enthalpy-driven” in each “PEG-400 + water” mixture studied.

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Section: Introductionmentioning

confidence: 99%

Solubility, Hansen Solubility Parameters and Thermodynamic Behavior of Emtricitabine in Various (Polyethylene Glycol-400 + Water) Mixtures: Computational Modeling and Thermodynamics

2020

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“…The comparative in vitro cytotoxicity of D+T NP vs. D+T solution was evaluated on the TZM-bl cell line using CellTiter-Glo ® luminescent assay method, as described previously (64). Briefly, the TZM-bl cells (10 4 cells/well) in complete HiDMEM medium and PBMCs (10 5 cells/well) in complete RPMI (Thermo Scientific; OK, USA) supplemented with 10% FBS, 1 × AA and 50 U/ml IL-2 (Sigma-Aldrich; MO, USA), were treated in triplicate respectively with D+T NP or D+T solution, at different concentrations (20, 10, 1, 0.1, 0.01 μg/mL each drug concentration) for 96 h. Similarly, the 5% DMSO treated cells and 1×PBS (treatment equal volume) treated cells were the positive and negative control, respectively.…”

Section: Methodsmentioning

confidence: 99%

“…The comparative in vitro prophylaxis (PrEP), i.e., protection study between D+T NP vs. D+T solution against HIV-1 NL4-3 , was performed on TZM-bl cells (an HIV-1 infection reporter cell line), and peripheral blood mononuclear cells (PBMCs) was evaluated by following standardized method (9, 64). Briefly, TZM-bl cells (10 4 cells/well) and PBMCs (10 5 cells/well) were seeded in 96-well plate and were treated with different concentrations of D+T (20, 10, 1, 0.1, 0.01 μg/mL each drug concentration) either as D+T NP or as D+T solution.…”

Section: Methodsmentioning

confidence: 99%

Targeted immuno-antiretroviral HIV therapeutic approach to provide dual protection and boosts cellular immunity: A proof-of-concept study

Mandal¹,

Prathipati²,

Belshan³

et al. 2020

Preprint

Self Cite

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Human immunodeficiency virus (HIV)-infected active and latent CCR5 expressing long-lived T-cells are the primary barrier to HIV/AIDS eradication. Broadly neutralizing antibodies and latency-reversing agents are the two most promising strategies emerging to achieve ‘functional cure’ against HIV infection. Antiretrovirals (ARVs) have shown to suppress plasma viral loads to non-detectable levels and above strategies have demonstrated a ‘functional cure’ against HIV infection is achievable. Both the above strategies are effective at inducing direct or immune-mediated cell death of latent HIV+ T-cells but have shown respective limitations. In this study, we designed a novel targeted ARVs-loaded nanoformulation that combines the CCR5 monoclonal antibody and antiretroviral drugs (ARV) as a dual protection strategy to promote HIV ‘functional cure’. The modified CCR5 monoclonal antibody (xfR5 mAb) surface-coated dolutegravir (DTG) and tenofovir alafenamide (TAF) loaded nanoformulation (xfR5-D+T NPs) were uniformly sized <250 nm, with 6.5 times enhanced antigen-binding affinity compared to naïve xfR5 mAb, and provided prolonged DTG and TAF intracellular retention (t1/2). The multivalent and sustained drug release properties of xfR5-D+T NPs enhance the protection efficiency against HIV by approximately 12, 3, and 5 times compared to naïve xfR5 mAb, D+T NP alone, and xfR5 NPs, respectively. Further, the nanoformulation demonstrated high binding-affinity to CCR5 expressing CD4+ cells, monocytes, and other HIV prone/latent T-cells by 25, 2, and 2 times, respectively. Further, the xfR5-D+T NPs during short-term pre-exposure prophylaxis induced a protective immunophenotype, i.e., boosted T-helper (Th), temporary memory (TM), and effector (E) sub-population. Moreover, treatment with xfR5-D+T NPs to HIV-infected T-cells induced a defensive/activated immunophenotype i.e., boosted naïve, Th, boosted central memory, TM, EM, E, and activated cytotoxic T-cells population. Therefore, this dual-action targeted mAb-ARV loaded nanoformulation could potentially become a multifactorial/multilayered solution to achieve a “functional cure.”

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“…The compound displayed an improved pharmacokinetic profile over pristine drugs in rats after intravenous dosing without loss of anti-HIV efficacy in vitro [96]. Mandal et al pursued a similar strategy with nanoparticles of PLGA encapsulating elvitegravir (EVG), emtricitabine (FTC) and tenofovir alafenamide (TAF), and found that this combination had HIV prevention effects in humanized mice [97][98][99].…”

Section: Long-acting Antiviral Prodrugsmentioning

confidence: 99%

The Potential of Long-Acting, Tissue-Targeted Synthetic Nanotherapy for Delivery of Antiviral Therapy Against HIV Infection

Andersen

Tolstrup

2020

Viruses

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Oral administration of a combination of two or three antiretroviral drugs (cART) has transformed HIV from a life-threatening disease to a manageable infection. However, as the discontinuation of therapy leads to virus rebound in plasma within weeks, it is evident that, despite daily pill intake, the treatment is unable to clear the infection from the body. Furthermore, as cART drugs exhibit a much lower concentration in key HIV residual tissues, such as the brain and lymph nodes, there is a rationale for the development of drugs with enhanced tissue penetration. In addition, the treatment, with combinations of multiple different antiviral drugs that display different pharmacokinetic profiles, requires a strict dosing regimen to avoid the emergence of drug-resistant viral strains. An intriguing opportunity lies within the development of long-acting, synthetic scaffolds for delivering cART. These scaffolds can be designed with the goal to reduce the frequency of dosing and furthermore, hold the possibility of potential targeting to key HIV residual sites. Moreover, the synthesis of combinations of therapy as one molecule could unify the pharmacokinetic profiles of different antiviral drugs, thereby eliminating the consequences of sub-therapeutic concentrations. This review discusses the recent progress in the development of long-acting and tissue-targeted therapies against HIV for the delivery of direct antivirals, and examines how such developments fit in the context of exploring HIV cure strategies.

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

Cited by 39 publications

References 34 publications

Solubility, Hansen Solubility Parameters and Thermodynamic Behavior of Emtricitabine in Various (Polyethylene Glycol-400 + Water) Mixtures: Computational Modeling and Thermodynamics

Solubility, Hansen Solubility Parameters and Thermodynamic Behavior of Emtricitabine in Various (Polyethylene Glycol-400 + Water) Mixtures: Computational Modeling and Thermodynamics

Targeted immuno-antiretroviral HIV therapeutic approach to provide dual protection and boosts cellular immunity: A proof-of-concept study

The Potential of Long-Acting, Tissue-Targeted Synthetic Nanotherapy for Delivery of Antiviral Therapy Against HIV Infection

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