July 2019
Volume 60, Issue 9
Free
ARVO Annual Meeting Abstract  |   July 2019
In vitro and in vivo delivery of a sustained release nanocarrier-based formulation of an MRTF/SRF inhibitor in conjunctival fibrosis
Author Affiliations & Notes
  • Cynthia Yu-Wai-Man
    King's College London, London, United Kingdom
    UCL Institute of Ophthalmology, London, United Kingdom
  • Scott Larsen
    Vahlteich Medicinal Chemistry Core, University of Michigan, Ann Arbor, Michigan, United States
  • Richard Neubig
    Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Michigan, United States
  • Kin Sheng Lim
    King's College London, London, United Kingdom
  • Aristides Tagalakis
    Edge Hill University, Ormskirk, United Kingdom
  • Footnotes
    Commercial Relationships   Cynthia Yu-Wai-Man, None; Scott Larsen, None; Richard Neubig, None; Kin Sheng Lim, None; Aristides Tagalakis, None
  • Footnotes
    Support  MRC Grant 535333
Investigative Ophthalmology & Visual Science July 2019, Vol.60, 5241. doi:
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      Cynthia Yu-Wai-Man, Scott Larsen, Richard Neubig, Kin Sheng Lim, Aristides Tagalakis; In vitro and in vivo delivery of a sustained release nanocarrier-based formulation of an MRTF/SRF inhibitor in conjunctival fibrosis. Invest. Ophthalmol. Vis. Sci. 2019;60(9):5241.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : Sustained drug delivery is a large unmet clinical need in glaucoma. We hypothesised that a nanocarrier formulation of an MRTF/SRF inhibitor, CCG-222740, could be used as a sustained release antifibrotic therapy in glaucoma filtration surgery.

Methods : Nanocarrier CCG-222740 was prepared by the thin film hydration technique using the DOTMA and DOPE liposomes in a 1:1:1 molar ratio (DOTMA:DOPE:CCG-222740). Nanocarrier size, zeta potential and morphology were determined by dynamic light scattering, laser Doppler anemometry and transmission electron microscopy, respectively. We tested the effects of nanocarrier CCG-222740 on ACTA2 gene expression using real-time qPCR and on cell viability in human conjunctival fibroblasts. Drug release studies were performed using high performance liquid chromatography. We validated our results using a randomised, prospective, masked-observer study of 18 New Zealand white rabbits undergoing glaucoma filtration surgery. The animals received intraoperative 0.2 mg/ml mitomycin-C [N=6] or a postoperative subconjunctival injection of 68 μg nanocarrier CCG-222740 [N=6] or empty liposomes [N=6]. Bleb morphology was recorded over 30 days. Tissue sections on day 30 were immunohistochemically assessed. We analysed our results using the Kaplan-Meier curve Log-rank test and Student’s t-test.

Results : The vesicles were spherical particles of 137.0 ± 7.1 (SEM) nm, +63.0 ± 1.5 mV and 0.39 ± 0.02 polydispersity index (Figure 1). In vitro, nanocarrier CCG-222740 was not cytotoxic and decreased ACTA2 gene by 61.0% (p=0.026) and 71.2% (p=0.033) at 5 and 10 μM, respectively, compared to empty liposomes. There was a sustained cumulative drug release of 32.1%, 45.1%, 63.7%, 79.8% and 93.1% at 1, 3, 6, 9 and 14 days. In vivo, nanocarrier CCG-222740 doubled bleb survival from 11.0 ± 0.6 days for empty liposomes to 22.0 ± 1.3 days (p=0.001). Nanocarrier CCG-222740 significantly decreased conjunctival scarring compared to empty liposomes using H&E, picrosirius red, Gomori’s trichrome and alpha smooth muscle actin staining. There were no adverse side effects and drug levels were undetectable in the aqueous and vitreous.

Conclusions : A nanocarrier formulation of an MRTF/SRF inhibitor represents a safe and sustained release drug delivery system that could be used to prolong bleb survival and to prevent conjunctival fibrosis after glaucoma filtration surgery.

This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.

 

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