A potential long-acting bictegravir loaded nano-drug delivery system for HIV-1 infection

A proof-of-concept study

Subhra Mandal, Pavan Kumar Prathipati, Michael A. Belshan, Christopher J. Destache

Research output: Contribution to journalArticle

Abstract

Bictegravir (BIC), a newly FDA-approved integrase strand transfer inhibitor (INSTI), as a single tablet regimen has proven efficacious in treating HIV-1 and SIV viruses, with reduced resistance. BIC clinical trials have not investigated its prophylaxis potency. This study investigates the HIV prevention potency of a novel long-acting BIC nano-formulation aimed to improve adherence. Poly (lactic-co-glycolic acid) loaded BIC nanoparticles (BIC NPs) were formulated using an oil-in-water emulsion methodology. BIC NPs were <200 nm in size, with 47.9 ± 6.9% encapsulation efficiency. A novel, sensitive and high throughput LC-MS/MS method was used to estimate intracellular pharmacokinetics (PK) of BIC NPs and compared to BIC solution demonstrated prolonged intracellular BIC retention. BIC NPs safety was assessed based on cytotoxicity. Further, in-vitro prevention study of BIC NPs vs BIC solution was assessed against HIV-1 NLX and HIV-1 ADA on TZM-bl cell line and PBMCs, respectively. BIC nanoencapsulation demonstrated elevated cellular cytotoxicity concentration (CC 50 : 2.25 μM (BIC solution) to 820.4 μM (BIC NPs)] and lowers HIV-1 inhibitory concentration [EC 50 : 0.604 μM (BIC solution) to 0.0038 μM (BIC NPs)) thereby improving selectivity index (SI) from 3.7 (BIC solution) to 215,789 (BIC NP) for TZM-bl cells. Comparable results in PBMCs were obtained where BIC NPs improved SI from 0.29 (BIC solution) to 523.33 (BIC NPs). This demonstrates long-acting BIC nano-formulation with sustained drug-release potency, improved BIC cytotoxicity and enhanced HIV-1 protection compared to BIC in solution.

Original languageEnglish (US)
Pages (from-to)83-88
Number of pages6
JournalAntiviral Research
Volume167
DOIs
StatePublished - Jul 1 2019

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Drug Delivery Systems
HIV Infections
HIV-1
Integrases
Emulsions
Nanoparticles
Tablets
Inhibitory Concentration 50
Oils
Pharmacokinetics
Clinical Trials
HIV
Viruses
Safety
Cell Line
Water

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Virology

Cite this

A potential long-acting bictegravir loaded nano-drug delivery system for HIV-1 infection : A proof-of-concept study. / Mandal, Subhra; Prathipati, Pavan Kumar; Belshan, Michael A.; Destache, Christopher J.

In: Antiviral Research, Vol. 167, 01.07.2019, p. 83-88.

Research output: Contribution to journalArticle

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abstract = "Bictegravir (BIC), a newly FDA-approved integrase strand transfer inhibitor (INSTI), as a single tablet regimen has proven efficacious in treating HIV-1 and SIV viruses, with reduced resistance. BIC clinical trials have not investigated its prophylaxis potency. This study investigates the HIV prevention potency of a novel long-acting BIC nano-formulation aimed to improve adherence. Poly (lactic-co-glycolic acid) loaded BIC nanoparticles (BIC NPs) were formulated using an oil-in-water emulsion methodology. BIC NPs were <200 nm in size, with 47.9 ± 6.9{\%} encapsulation efficiency. A novel, sensitive and high throughput LC-MS/MS method was used to estimate intracellular pharmacokinetics (PK) of BIC NPs and compared to BIC solution demonstrated prolonged intracellular BIC retention. BIC NPs safety was assessed based on cytotoxicity. Further, in-vitro prevention study of BIC NPs vs BIC solution was assessed against HIV-1 NLX and HIV-1 ADA on TZM-bl cell line and PBMCs, respectively. BIC nanoencapsulation demonstrated elevated cellular cytotoxicity concentration (CC 50 : 2.25 μM (BIC solution) to 820.4 μM (BIC NPs)] and lowers HIV-1 inhibitory concentration [EC 50 : 0.604 μM (BIC solution) to 0.0038 μM (BIC NPs)) thereby improving selectivity index (SI) from 3.7 (BIC solution) to 215,789 (BIC NP) for TZM-bl cells. Comparable results in PBMCs were obtained where BIC NPs improved SI from 0.29 (BIC solution) to 523.33 (BIC NPs). This demonstrates long-acting BIC nano-formulation with sustained drug-release potency, improved BIC cytotoxicity and enhanced HIV-1 protection compared to BIC in solution.",
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