In vitro Study on Synergistic Interactions Between Free and Encapsulated Q-Griffithsin and Antiretrovirals Against HIV-1 Infection.
Anti-HIV Agents
/ pharmacology
Anti-Retroviral Agents
/ pharmacology
Cell Death
/ drug effects
Cell Line
Drug Compounding
Drug Liberation
Drug Synergism
Female
HIV Infections
/ drug therapy
HIV-1
/ drug effects
Humans
Inhibitory Concentration 50
Lectins
/ pharmacology
Nanoparticles
/ chemistry
Particle Size
Plant Lectins
Polylactic Acid-Polyglycolic Acid Copolymer
/ chemistry
Pyrimidines
/ pharmacology
Raltegravir Potassium
/ pharmacology
Recombinant Proteins
Tenofovir
/ pharmacology
HIV-1 prevention
antiretrovirals
electrospun fibers
griffithsin
microbicide
nanoparticles
synergy
Journal
International journal of nanomedicine
ISSN: 1178-2013
Titre abrégé: Int J Nanomedicine
Pays: New Zealand
ID NLM: 101263847
Informations de publication
Date de publication:
2021
2021
Historique:
received:
22
10
2020
accepted:
19
12
2020
entrez:
24
2
2021
pubmed:
25
2
2021
medline:
13
3
2021
Statut:
epublish
Résumé
Human immunodeficiency virus (HIV) remains a persistent global challenge, impacting 38 million people worldwide. Antiretrovirals (ARVs) including tenofovir (TFV), raltegravir (RAL), and dapivirine (DAP) have been developed to prevent and treat HIV-1 via different mechanisms of action. In parallel, a promising biological candidate, griffithsin (GRFT), has demonstrated outstanding preclinical safety and potency against HIV-1. While ARV co-administration has been shown to enhance virus inhibition, synergistic interactions between ARVs and the oxidation-resistant variant of GRFT (Q-GRFT) have not yet been explored. Here, we co-administered Q-GRFT with TFV, RAL, and DAP, in free and encapsulated forms, to identify unique protein-drug synergies. Nanoparticles (NPs) were synthesized using a single or double-emulsion technique and release from each formulation was assessed in simulated vaginal fluid. Next, each ARV, in free and encapsulated forms, was co-administered with Q-GRFT or Q-GRFT NPs to evaluate the impact of co-administration in HIV-1 pseudovirus assays, and the combination indices were calculated to identify synergistic interactions. Using the most synergistic formulations, we investigated the effect of agent incorporation in NP-fiber composites on release properties. Finally, NP safety was assessed in vitro using MTT assay. All active agents were encapsulated in NPs with desirable encapsulation efficiency (15-100%), providing ~20% release over 2 weeks. The co-administration of free Q-GRFT with each free ARV resulted in strong synergistic interactions, relative to each agent alone. Similarly, Q-GRFT NP and ARV NP co-administration resulted in synergy across all formulations, with the most potent interactions between encapsulated Q-GRFT and DAP. Furthermore, the incorporation of Q-GRFT and DAP in NP-fiber composites resulted in burst release of DAP and Q-GRFT with a second phase of Q-GRFT release. Finally, all NP formulations exhibited safety in vitro. This work suggests that Q-GRFT and ARV co-administration in free or encapsulated forms may improve efficacy in achieving prophylaxis.
Identifiants
pubmed: 33623382
doi: 10.2147/IJN.S287310
pii: 287310
pmc: PMC7894819
doi:
Substances chimiques
Anti-HIV Agents
0
Anti-Retroviral Agents
0
Lectins
0
Plant Lectins
0
Pyrimidines
0
Recombinant Proteins
0
q-griffithsin
0
Polylactic Acid-Polyglycolic Acid Copolymer
1SIA8062RS
Raltegravir Potassium
43Y000U234
Tenofovir
99YXE507IL
Dapivirine
TCN4MG2VXS
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
1189-1206Subventions
Organisme : NIGMS NIH HHS
ID : P20 GM125504
Pays : United States
Informations de copyright
© 2021 Minooei et al.
Déclaration de conflit d'intérêts
The authors declare they have no competing interests.
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