Long-acting parenteral combination antiretroviral loaded nano-drug delivery system to treat chronic HIV-1 infection: A humanized mouse model study

Mandal, Subhra; Kang, Guobin; Prathipati, Pavan Kumar; Wang, Fan; Li, Qingsheng; Destache, Christopher J.

doi:10.1016/j.antiviral.2018.06.005

Cited by 39 publications

(29 citation statements)

References 28 publications

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“…Antiviral therapy dCA [45,56] EFdA [57] RAL [45] PD-1 mAb [58] PG16 bNAb [59] PGT121 bNAb [60] 3TC, TDF [61] AZT, ddI, IDV [52] FTC, RPV, DTG [46,57] FTC, TAF, EVG [62] FTC, TDF, DTG [37,46,51,53,63] FTC, TDF, RAL [37,46,51,63] FTC, TDF, RAL, 3B3(Fv)-PE38 immunotoxin [64] FTC, TDF, RAL, IFNα14 [61,65] Pre-exposure prophylaxis (PrEP) C5A peptide [66] Cc-griffithsin [67] CD4 AsiCs [68] CD4-expressing Lactobacillus acidophilus [69] CD4mc P-III-48 [70] DTG-ultra LA [71] EFdA [72] G2-S16 PCD [73] IgA [74] MVC [75] RAL-LA [76] RPV-LA [39,77] siCCR5 LFA-1 I-tsNP [78] TNV gel [79][80][81] VRC01 bNAb [82] FTC, TAF [83] FTC, TDF [36,43,84,85] TAF, EVG…”

Section: Strategy Therapeutic Agent(s) Reference(s)mentioning

confidence: 99%

Moving beyond the mousetrap: current and emerging humanized mouse and rat models for investigating prevention and cure strategies against HIV infection and associated pathologies

et al. 2020

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The development of safe and effective combination antiretroviral therapies for human immunodeficiency virus (HIV) infection over the past several decades has significantly reduced HIV-associated morbidity and mortality. Additionally, antiretroviral drugs have provided an effective means of protection against HIV transmission. Despite these advances, significant limitations exist; namely, the inability to eliminate HIV reservoirs, the inability to reverse lymphoid tissues damage, and the lack of an effective vaccine for preventing HIV transmission. Evaluation of the safety and efficacy of therapeutics and vaccines for eliminating HIV reservoirs and preventing HIV transmission requires robust in vivo models. Since HIV is a human-specific pathogen, that targets hematopoietic lineage cells and lymphoid tissues, in vivo animal models for HIV-host interactions require incorporation of human hematopoietic lineage cells and lymphoid tissues. In this review, we will discuss the construction of mouse models with human lymphoid tissues and/or hematopoietic lineage cells, termed, human immune system (HIS)-humanized mice. These HIS-humanized mouse models can support the development of functional human innate and adaptive immune cells, along with primary (thymus) and secondary (spleen) lymphoid tissues. We will discuss applications of HIS-humanized mouse models in evaluating the safety and efficacy of therapeutics against HIV reservoirs and associated immunopathology, and delineate the human immune response elicited by candidate HIV vaccines. In addition to focusing on how these HIS-humanized mouse models have already furthered our understanding of HIV and contributed to HIV therapeutics development, we discuss how emerging HIS-humanized rat models could address the limitations of HIS-mouse models.

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Section: Strategy Therapeutic Agent(s) Reference(s)mentioning

confidence: 99%

Moving beyond the mousetrap: current and emerging humanized mouse and rat models for investigating prevention and cure strategies against HIV infection and associated pathologies

et al. 2020

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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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“…The % drug entrapment efficiency (%EE) of DTG and TAF in D+T NPs and xfR5-D+T NPs were evaluated by high-performance liquid chromatography (HPLC) instrument by following published methodology (30, 31, 60). Briefly, 1 mg of D+T NPs dissociated in 50 μL DMSO and mobile phase (25mM KH 2 PO 4 45%: ACN 55%) added to get 10% DMSO final concentration in the injection volume (20 μL).…”

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

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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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Long-acting parenteral combination antiretroviral loaded nano-drug delivery system to treat chronic HIV-1 infection: A humanized mouse model study

Cited by 39 publications

References 28 publications

Moving beyond the mousetrap: current and emerging humanized mouse and rat models for investigating prevention and cure strategies against HIV infection and associated pathologies

Moving beyond the mousetrap: current and emerging humanized mouse and rat models for investigating prevention and cure strategies against HIV infection and associated pathologies

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

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