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Biodistribution and Pharmacokinetics of Dapivirine-Loaded Nanoparticles after Vaginal Delivery in Mice

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ABSTRACT

Purpose

To assess the potential of polymeric nanoparticles (NPs) to affect the genital distribution and local and systemic pharmacokinetics (PK) of the anti-HIV microbicide drug candidate dapivirine after vaginal delivery.

Methods

Dapivirine-loaded, poly(ethylene oxide)-coated poly(epsilon-caprolactone) (PEO-PCL) NPs were prepared by a nanoprecipitation method. Genital distribution of NPs and their ability to modify the PK of dapivirine up to 24 h was assessed after vaginal instillation in a female mouse model. Also, the safety of NPs upon daily administration for 14 days was assessed by histological analysis and chemokine/cytokine content in vaginal lavages.

Results

PEO-PCL NPs (180–200 nm) were rapidly eliminated after administration but able to distribute throughout the vagina and lower uterus, and capable of tackling mucus and penetrate the epithelial lining. Nanocarriers modified the PK of dapivirine, with higher drug levels being recovered from vaginal lavages and vaginal/lower uterine tissues as compared to a drug suspension. Systemic drug exposure was reduced when NPs were used. Also, NPs were shown safe upon administration for 14 days.

Conclusions

Dapivirine-loaded PEO-PCL NPs were able to provide likely favorable genital drug levels, thus attesting the potential value of using this vaginal drug delivery nanosystem in the context of HIV prophylaxis.

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Abbreviations

λz :

Apparent terminal elimination rate constant

AE%:

Association efficiency

AUC0.25-24h :

Area under the concentration-time curve between 15 min and 24 h

C max :

Maximum observed concentration

DL%:

Drug loading

EC50 :

Half maximal effective concentration

F rel :

Relative bioavailability

IL:

Interleukin

KC:

Keratinocyte-derived chemokine

MIP-1α:

Macrophage inflammatory protein

MPPs:

Mucus-penetrating particles

N-9:

Nonoxynol-9

NPs:

Nanoparticles

PBS:

Phosphate buffered saline

PCL:

Poly(ε-caprolactone)

PD:

Pharmacodynamics

PdI:

Polydispersity index

PEG:

Poly(ethylene glycol)

PEO:

Poly(ethylene oxide)

PK:

Pharmacokinetics

PLGA:

Poly(D,L-lactide-co-glycolide)

PPO:

Poly(propylene oxide)

PrEP:

Pre-exposure prophylaxis

rhod-123-PCL:

Rhodamine-123-labeled poly(ε-caprolactone)

s.d.:

Standard deviation

s.e.m.:

Standard error of the mean

t 1/2β :

Terminal elimination half-life

t max :

C max time

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ACKNOWLEDGMENTS AND DISCLOSURES

José das Neves gratefully acknowledges Fundação para a Ciência e a Tecnologia (FCT), Portugal for financial support (grant SFRH/BD/43393/2008). This work was supported by a grant from FCT (VIH/SAU/0021/2011). The authors would like to express their gratitude to Catarina Ferreira (University of Beira Interior, Covilhã, Portugal) for histology slides preparation. Dapivirine was kindly provided by IPM. Dapivirine was originally developed by Tibotec Pharmaceuticals and licensed to IPM.

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Authors and Affiliations

  1. IINFACTS – Instituto de Investigação e Formação Avançada em Ciências e Tecnologias da Saúde, Instituto Superior de Ciências da Saúde-Norte, CESPU, Rua Central de Gandra, 1317, 4585-116, Gandra, Portugal

    José das Neves, Francisca Araújo & Bruno Sarmento

  2. Laboratory of Pharmaceutical Technology, Faculty of Pharmacy, University of Porto, Porto, Portugal

    José das Neves, Fernanda Andrade & Maria Fernanda Bahia

  3. INEB – Instituto de Engenharia Biomédica, Porto, Portugal

    Francisca Araújo & Bruno Sarmento

  4. Department of Pharmaceutical Sciences, School of Pharmacy, Northeastern University, Boston, Massachusetts, 02115, USA

    Mansoor Amiji

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  1. José das Neves
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  2. Francisca Araújo
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  4. Mansoor Amiji
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  5. Maria Fernanda Bahia
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  6. Bruno Sarmento
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Correspondence to José das Neves.

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ESM 1

Detailed information on (1) sectioning of the mouse female genital tract, (2) methods used for tissue processing for fluorescence microscopy, and (3) validation parameters of the HPLC-UV method used is available. Also, methods and results for the 14-day toxicity assessment of dapivirine-loaded NPs and alcian blue staining of mucus present at the vaginal mucosa after washing are included. (DOCX 6593 kb)

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das Neves, J., Araújo, F., Andrade, F. et al. Biodistribution and Pharmacokinetics of Dapivirine-Loaded Nanoparticles after Vaginal Delivery in Mice. Pharm Res 31, 1834–1845 (2014). https://doi.org/10.1007/s11095-013-1287-x

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  • DOI: https://doi.org/10.1007/s11095-013-1287-x

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