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Polymeric Nanoparticles Affect the Intracellular Delivery, Antiretroviral Activity and Cytotoxicity of the Microbicide Drug Candidate Dapivirine

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ABSTRACT

Purpose

To assess the intracellular delivery, antiretroviral activity and cytotoxicity of poly(ε-caprolactone) (PCL) nanoparticles containing the antiretroviral drug dapivirine.

Methods

Dapivirine-loaded nanoparticles with different surface properties were produced using three surface modifiers: poloxamer 338 NF (PEO), sodium lauryl sulfate (SLS) and cetyl trimethylammonium bromide (CTAB). The ability of nanoparticles to promote intracellular drug delivery was assessed in different cell types relevant for vaginal HIV transmission/microbicide development. Also, antiretroviral activity of nanoparticles was determined in different cell models, as well as their cytotoxicity.

Results

Dapivirine-loaded nanoparticles were readily taken up by different cells, with particular kinetics depending on the cell type and nanoparticles, resulting in enhanced intracellular drug delivery in phagocytic cells. Different nanoparticles showed similar or improved antiviral activity compared to free drug. There was a correlation between increased antiviral activity and increased intracellular drug delivery, particularly when cell models were submitted to a single initial short-course treatment. PEO-PCL and SLS-PCL nanoparticles consistently showed higher selectivity index values than free drug, contrasting with high cytotoxicity of CTAB-PCL.

Conclusions

These results provide evidence on the potential of PCL nanoparticles to affect in vitro toxicity and activity of dapivirine, depending on surface engineering. Thus, this formulation approach may be a promising strategy for the development of next generation microbicides.

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Abbreviations

CC50 :

50% cytotoxic concentration

CTAB:

cetyl trimethylammonium bromide

DIC:

differential interference contrast

DLS:

dynamic light scattering

DMSO:

dimethyl sulfoxide

EC50 :

50% effective concentration

FACS:

fluorescence-activated cell sorting

FBS:

fetal bovine serum

LDH:

lactate dehydrogenase

MOI:

multiplicity of infection

Mo-DC:

monocyte-derived dendritic cells

Mo/Mac:

monocyte/macrophages

MTS:

3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium assay

NNRTI:

non-nucleoside reverse transcriptase inhibitor

PBL:

peripheral blood lymphocytes

PBMCs:

peripheral blood mononuclear cells

PBS:

phosphate buffered saline

PCL:

poly(ε-caprolactone)

PdI:

polydispersity index

PEO:

poly(ethylene oxide)

PHA:

phytohemagglutinin

PPO:

poly(propylene oxide)

SEM:

scanning electron microscopy

SLS:

sodium lauryl sulfate

SVF:

simulated vaginal fluid

WST-1:

water soluble tetrazolium-1 assay

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ACKNOWLEDGMENTS & DISCLOSURES

José das Neves gratefully acknowledges Fundação para a Ciência e a Tecnologia, Portugal for financial support (grant SFRH/BD/43393/2008). Kevin K. Ariën and Guido Vanham are supported by research grants from the Fund for Scientific Research Flanders (FWO), the Agence Nationale de Recherches sur le SIDA et les hépatites virales (ANRS), and EU-FP7 CHAARM. Dapivirine was originally developed by Tibotec Pharmaceuticals and was licensed to the International Partnership for Microbicides under a royalty-free agreement for the development of vaginal microbicides. We express our gratitude to Jing Xu for SEM imaging at the Nanomaterials Characterization Facility, Northeastern University.

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Authors and Affiliations

  1. Laboratory of Pharmaceutical Technology, LTF/CICF Faculty of Pharmacy, University of Porto, Rua Aníbal Cunha, 164, 4050-047, Porto, Portugal

    José das Neves, Maria Fernanda Bahia & Bruno Sarmento

  2. Virology Unit, Department of Microbiology, Institute of Tropical Medicine, Antwerpen, Belgium

    Johan Michiels, Kevin K. Ariën & Guido Vanham

  3. Department of Biomedical Sciences, Faculty of Pharmacology Biomedical and Veterinary Sciences, University of Antwerpen, Antwerpen, Belgium

    Guido Vanham

  4. Faculty of Medicine and Pharmacology, University of Brussels, Brussels, Belgium

    Guido Vanham

  5. Department of Pharmaceutical Sciences, School of Pharmacy, Northeastern University, Boston, Massachusetts, USA

    Mansoor Amiji

  6. CICS—Centro de Investigação em Ciências da Saúde, Department of Pharmaceutical Sciences Instituto Superior de Ciências da Saúde-Norte, Gandra, Portugal

    Bruno Sarmento

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  1. José das Neves
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Correspondence to José das Neves.

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das Neves, J., Michiels, J., Ariën, K.K. et al. Polymeric Nanoparticles Affect the Intracellular Delivery, Antiretroviral Activity and Cytotoxicity of the Microbicide Drug Candidate Dapivirine. Pharm Res 29, 1468–1484 (2012). https://doi.org/10.1007/s11095-011-0622-3

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  • DOI: https://doi.org/10.1007/s11095-011-0622-3

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