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Toxicity and in vivo release profile of sirolimus from implants into the vitreous of rabbits’ eyes

  • Mayara Rodrigues Brandão De Paiva
  • Nayara Almeida Lage
  • Maria Carolina Andrade Guerra
  • Marcos Paulo Gomes Mol
  • Marcela Coelho Silva Ribeiro
  • Gustavo De Oliveira Fulgêncio
  • Dawidson A. Gomes
  • Isabela Da Costa César
  • Sílvia Ligório FialhoEmail author
  • Armando Silva-Cunha
Original Research Article
  • 28 Downloads

Abstract

Purpose

To assess the in vivo release profile and the retinal toxicity of a poly (lactic-co-glycolic acid) (PLGA) sustained-release sirolimus (SRL) intravitreal implant in normal rabbit eyes.

Methods

PLGA intravitreal implants containing or not SRL were prepared, and the viability of ARPE-19 and hES-RPE human retinal cell lines was examined after 24 and 72 h of exposure to implants. New Zealand rabbits were randomly divided into two groups that received intravitreal implants containing or not SRL. At each time point (1–8 weeks), four animals from the SRL group were euthanized, the vitreous was collected, and drug concentration was calculated. Clinical evaluation of the eyes was performed weekly for 8 weeks after administration. Electroretinography (ERG) was recorded in other eight animals, four for each group, at baseline and at 24 h, 1, 4, 6, and 8 weeks after the injection. ERG was carried out using scotopic and photopic protocols. The safety of the implants was assessed using statistical analysis of the ERG parameters (a and b waves, a and b implicit time, B/A ratio, oscillatory potential, and Naka–Rushton analysis) comparing the functional integrity of the retina between the PLGA and SRL-PLGA groups. After the last electrophysiological assessment, the rabbits were euthanized and retinal histopathology was realized.

Results

After 24 and 72 h of incubation with PLGA or SRL-PLGA implants, ARPE-19 and hES-RPE cells showed viability over 70%. The maximum concentration of SRL (199.8 ng/mL) released from the device occurred within 4 weeks. No toxic effects of the implants or increase in the intraocular pressure was observed through clinical evaluation of the eye. ERG responses showed no significant difference between the eyes that received PLGA or SRL-PLGA implants at baseline and throughout the 8 weeks of follow-up. No remarkable difference in retinal histopathology was detected in rabbit eyes treated with PLGA or SRL-PLGA implants.

Conclusions

Intravitreal PLGA or SRL-PLGA implants caused no significant reduction in cell viability and showed no evident toxic effect on the function or structure of the retina of the animals. SRL was released from PLGA implant after application in the vitreous of rabbits during 8 weeks.

Keywords

Cell viability Electroretinography Intravitreal drug delivery Sirolimus Biodegradable implant Toxicity 

Notes

Acknowledgements

The authors thank CNPq/MCT (Brazil), Fapemig (Brazil), and CAPES/MEC (Brazil) for the financial support.

Compliance with ethical standards

Conflicts of interest

The authors declare that they have no conflict of interest.

Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

Informed consent

Informed consent was not applicable.

Statement of human rights

This article does not contain any studies with human participants performed by any of the authors.

Statement on the welfare of animals

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted.

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Mayara Rodrigues Brandão De Paiva
    • 1
  • Nayara Almeida Lage
    • 1
  • Maria Carolina Andrade Guerra
    • 2
  • Marcos Paulo Gomes Mol
    • 2
  • Marcela Coelho Silva Ribeiro
    • 1
  • Gustavo De Oliveira Fulgêncio
    • 1
  • Dawidson A. Gomes
    • 3
  • Isabela Da Costa César
    • 1
  • Sílvia Ligório Fialho
    • 2
    Email author
  • Armando Silva-Cunha
    • 1
  1. 1.Faculty of PharmacyFederal University of Minas GeraisBelo HorizonteBrazil
  2. 2.Pharmaceutical Research and DevelopmentEzequiel Dias FoundationBelo HorizonteBrazil
  3. 3.Department of Biochemistry and ImmunologyFederal University of Minas GeraisBelo HorizonteBrazil

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