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Ocular safety of Intravitreal Clindamycin Hydrochloride Released by PLGA Implants

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ABSTRACT

Background

Drug ocular toxicity is a field that requires attention. Clindamycin has been injected intravitreally to treat ocular toxoplasmosis, the most common cause of eye posterior segment infection worldwide. However, little is known about the toxicity of clindamycin to ocular tissues. We have previously showed non intraocular toxicity in rabbit eyes of poly(lactic-co-glycolic acid) (PLGA) implants containing clindamycin hydrochloride (CLH) using only clinical macroscotopic observation. In this study, we investigated the in vivo biocompatibility of CLH-PLGA implants at microscotopic, cellular and molecular levels.

Methods

Morphology of ARPE-19 and MIO-M1 human retinal cell lines was examined after 72 h exposure to CLH-PLGA implant. Drug delivery system was also implanted in the vitreous of rat eyes, retinal morphology was evaluated in vivo and ex vivo. Morphology of photoreceptors and inflammation was assessed using immunofluorescence and real-time PCR.

Results

After 72 h incubation with CLH-PLGA implant, ARPE-19 and MIO-M1 cells preserved the actin filament network and cell morphology. Rat retinas displayed normal lamination structure at 30 days after CLH-PLGA implantation. There was no apoptotic cell and no loss in neuron cells. Cones and rods maintained their normal structure. Microglia/macrophages remained inactive. CLH-PLGA implantation did not induce gene expression of cytokines (IL-1β, TNF-α, IL-6), VEGF, and iNOS at day 30.

Conclusion

These results demonstrated the safety of the implant and highlight this device as a therapeutic alternative for the treatment of ocular toxoplasmosis.

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Abbreviations

ARPE-19:

Human retinal pigment epithelial cell line

CLH:

Clindamycin hydrochloride

DAPI:

2-(4-amidinophenyl)-1H -indole-6-carboxamidine

DMEM/F-12:

Dulbecco’s modified eagle medium: nutrient mixture F-12

ERG:

Electroretinogram

FBS:

Fetal bovine serum

FITC:

Fluorescein isothiocyanate

GCL:

Ganglion cell layer

HAM:

Human amniotic membrane

HEPES:

4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid

HPRT:

Hypoxanthine phosphoribosyltransferase

IBA-1:

Ionized calcium binding adaptor molecule 1

IL-1β:

Interleukin 1 beta

IL-6:

Interleukin 6

INL:

Inner nuclear layer

iNOS:

Inducible nitric oxide synthase

IP:

Propidium iodide

MIO-M1:

Human Müller cell line

OCT:

Optical coherence tomography

OLN:

Outer nuclear layer

PBS:

Phosphate-buffered saline

PCR:

Polymerase chain reaction

PLGA:

Poly(lactic-co-glycolic acid)

PNA:

Peanut Agglutinin

SD:

Standard deviation

TNF-α:

Tumor necrosis factor alpha

TUNEL:

Terminal deoxynucleotidyl transferase dUTP nick end labeling

VEGF:

Vascular endothelial growth factor

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ACKNOWLEDGMENTS AND DISCLOSURES

The authors would like to acknowledge the financial support received from the following institutions: (Brazil), FAPEMIG (Minas Gerais – Brazil), Pró-reitoria de Pesquisa da Universidade Federal de Minas Gerais (Minas Gerais – Brazil), CAPES (Bolsistas da CAPES-Brasília/Brazil).

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Authors and Affiliations

  1. Faculty of Pharmacy, Federal University of Minas Gerais, Av. Presidente Antônio Carlos, 6627, 31270-901, Belo Horizonte, Minas Gerais, Brazil

    Gabriella M. Fernandes-Cunha & Armando Silva-Cunha

  2. INSERM UMRS 1138, Team 17, Centre de Recherche des Cordeliers, 75006, Paris, France

    Gabriella M. Fernandes-Cunha, Gisele Rodrigues da Silva, Min Zhao & Francine Behar-Cohen

  3. Pierre and Marie Curie University, 75005, Paris, France

    Gabriella M. Fernandes-Cunha, Gisele Rodrigues da Silva, Min Zhao & Francine Behar-Cohen

  4. Paris Descartes University, 75006, Paris, France

    Gabriella M. Fernandes-Cunha, Gisele Rodrigues da Silva, Min Zhao & Francine Behar-Cohen

  5. Pharmaceutical and Biotechnological Development, Ezequiel Dias Foundation, Belo Horizonte, Minas Gerais, Brazil

    Silvia Ligório Fialho

  6. Faculty of Pharmacy, Federal University of São João Del Rei, Divinópolis, Minas Gerais, Brazil

    Gisele Rodrigues da Silva

Authors
  1. Gabriella M. Fernandes-Cunha
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  2. Silvia Ligório Fialho
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  3. Gisele Rodrigues da Silva
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  4. Armando Silva-Cunha
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  5. Min Zhao
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  6. Francine Behar-Cohen
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Corresponding author

Correspondence to Gabriella M. Fernandes-Cunha.

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Fernandes-Cunha, G.M., Fialho, S.L., da Silva, G.R. et al. Ocular safety of Intravitreal Clindamycin Hydrochloride Released by PLGA Implants. Pharm Res 34, 1083–1092 (2017). https://doi.org/10.1007/s11095-017-2118-2

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  • DOI: https://doi.org/10.1007/s11095-017-2118-2

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