Nanoencapsulation introduces long-acting phenomenon to tenofovir alafenamide and emtricitabine drug combination: A comparative pre-exposure prophylaxis efficacy study against HIV-1 vaginal transmission

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

doi:10.1016/j.jconrel.2018.12.027

Cited by 42 publications

(58 citation statements)

References 34 publications

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“…The combination or dual protection of xfR5-D+T NP demonstrates more rigorous protection compared to only blocking CCR5 receptors on T-cells by multimeric CCR5 T-cell blocking, i.e., 5.5 times higher; and ARV induced HIV protection by treating with D+T NP alone, i.e., 3.5 times compared to ARV by D+T NP alone. Further, it is well established (9, 10, 30, 31) and our study also reflects (Table 4), that reduced cytotoxic effect and the increased protection efficacy against HIV, widens the therapeutic index of xfR5-D+T NPs against HIV-1 virus. The enhanced high therapeutic index, therefore, advocates the potency of xfR5-D+T NPs as an advanced HIV therapeutic.…”

Section: Discussionsupporting

confidence: 80%

“…The CCR5 targeted cARV loaded NPs were formulated by using standardized methodology with some modification (9, 10). To conjugate targeting molecule on ARV loaded NP’s surface, NHS functionalized NP loaded with DTG+TAF were formulated (Figure 1).…”

Section: Resultsmentioning

confidence: 99%

“…The nanoencapsulation of ARV drugs has known to reduce the toxicity of naïve drugs (9, 10, 30, 31). A comparative cytotoxicity study performed on TZM-bl cells and primary peripheral blood mononuclear cells (PBMCs) (Table 4).…”

Section: Resultsmentioning

confidence: 99%

“…The TZM-bl cell line obtained from the National Institutes of Health (NIH) acquired immunodeficiency syndrome (AIDS) reagent program is a JC53-bl (clone 13)/HeLa cell line that are phenotypic similar to HIV-1 infecting cell type (stably overexpresses CD4 and CCR5 receptor). TZM-bl cells were maintained in HiDMEM supplemented with 10% FBS and 1× AA, as standard protocol (9, 10). Whereas, peripheral blood mononuclear cells (PBMCs) were purchased from AllCells ® (Alameda, CA, USA) and maintained in RPMI 1640 supplemented with 10% FBS, 1×AA and 50 U/ml IL-2.…”

Section: Methodsmentioning

confidence: 99%

“…Recent studies have demonstrated designing a long-acting (LA) ARV delivery system would boost the HIV prevention and treatment strategy (6–9). The LA ARV delivery system has shown to enhance drug-solubility, stability, biodistribution, pharmacokinetics, efficiency, and concurrent drug safety, due to reduced ARV associated side-effects, such as mitochondrial toxicity, renal abnormality, and reduced bone mineral density (10–12). Even though LA ARV nanoparticles (NPs) are promising to be a successful injectable LA antiretroviral candidate, these systems still need to show a good tolerability profile.…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Discussionsupporting

confidence: 80%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

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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Injectable controlled‐release systems for the prevention and treatment of infectious diseases

Kunkel,

McHugh

2023

J Biomedical Materials Res

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Pharmaceutical drugs, including vaccines, pre‐ and post‐exposure prophylactics, and chronic drug therapies, are crucial tools in the prevention and treatment of infectious diseases. These drugs have the ability to increase survival and improve patient quality of life; however, infectious diseases still accounted for more than 10.2 million deaths in 2019 before the COVID‐19 pandemic. High mortality can be, in part, attributed to challenges in the availability of adequate drugs and vaccines, limited accessibility, poor drug bioavailability, the high cost of some treatments, and low patient adherence. A majority of these factors are logistical rather than technical challenges, providing an opportunity for existing drugs and vaccines to be improved through formulation. Injectable controlled‐release drug delivery systems are one class of formulations that have the potential to overcome many of these limitations by releasing their contents in a sustained manner to reduce the need for frequent re‐administration and improve clinical outcomes. This review provides an overview of injectable controlled drug delivery platforms, including microparticles, nanoparticles, and injectable gels, detailing recent developments using these systems for single‐injection vaccination, long‐acting prophylaxis, and sustained‐release treatments for infectious disease.

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Preparation, Controlled Drug Release, and Cell Viability Evaluation of Tenofovir Alafenamide‐Loaded Chitosan Nanoparticles

et al. 2021

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Tenofovir alafenamide (TAF) is used as a hepatitis B virus (HBV) nucleotide reverse transcriptase inhibitor for the treatment of chronic HBV infection. However, the use of TAF suffers from its poor solubility and low bioavailability. Therefore, this study prepared and characterized chitosan nanoparticles (CHS NPs) loaded with TAF. Morphological findings demonstrated that CHS NPs are roughly spherical and homogeneous in shape. Besides, TAF‐loaded CHS NPs displayed the hydrodynamic diameter, zeta potential, and PDI of approximately 340 nm, 48.9 mV, and 0.65, respectively. The encapsulation efficiency is at about 50%, and TAF is released about 93% at the end of 80 hours at pH 7.4. In addition, human hepatocellular carcinoma cells (HepG2) are used for cell viability studies and it is observed that TAF‐loaded CHS NPs has 1.24 times less viable cells as compared to the control. Collectively, TAF‐loaded CHS NPs could be used as an efficient formulation for the treatment of chronic HBV infection.

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Nanoencapsulation introduces long-acting phenomenon to tenofovir alafenamide and emtricitabine drug combination: A comparative pre-exposure prophylaxis efficacy study against HIV-1 vaginal transmission

Cited by 42 publications

References 34 publications

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

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

Injectable controlled‐release systems for the prevention and treatment of infectious diseases

Preparation, Controlled Drug Release, and Cell Viability Evaluation of Tenofovir Alafenamide‐Loaded Chitosan Nanoparticles

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