In vitro and in vivo delivery of a sustained release nanocarrier-based formulation of an MRTF/SRF inhibitor in conjunctival fibrosis

Tagalakis, Aristides, Madaan, Shivam, Larsen, Scott D., Neubig, Richard R., Khaw, Peng T. and Yu-Wai-Man, Cynthia (2018) In vitro and in vivo delivery of a sustained release nanocarrier-based formulation of an MRTF/SRF inhibitor in conjunctival fibrosis. Journal of Nanobiotechnology, 16 (97). ISSN 1477-3155 DOI https://doi.org/10.1186/s12951-018-0425-3

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Abstract

Background: Sustained drug delivery is a great unmet clinical need in glaucoma. Here, we incorporated a Myocardin-Related Transcription Factor/Serum Response Factor inhibitor, CCG-222740, into slow release large unilamellar vesicles derived from the liposomes DOTMA (1,2-di-O-octadecenyl-3-trimethylammonium propane) and DOPC (1,2-dioleoyl-sn-glycero-3-phosphocholine), and tested their effects in vitro and in vivo. Results: The vesicles were spherical particles of around 130 nm and were strongly cationic. A large amount of inhibitor could be incorporated into the vesicles. We showed that the nanocarrier CCG-222740 formulation gradually released the inhibitor over 14 days using high performance liquid chromatography. Nanocarrier CCG-222740 significantly decreased ACTA2 gene expression and was not cytotoxic in human conjunctival fibroblasts. In vivo, nanocarrier CCG-222740 doubled the bleb survival from 11.0 ± 0.6 days to 22.0 ± 1.3 days (p = 0.001), decreased conjunctival scarring and did not have any local or systemic adverse effects in a rabbit model of glaucoma filtration surgery. Conclusions: Our study demonstrates proof-of-concept that a nanocarrier-based formulation efficiently achieves a sustained release of a Myocardin-Related Transcription Factor/Serum Response Factor inhibitor and prevents conjunctival fibrosis in an established rabbit model of glaucoma filtration surgery.

Item Type: Article
Additional Information: This research was supported by the Medical Research Council (Grant 535333) and King’s College London. This work was also supported by the Data Science STEM Research Centre at Edge Hill University.
Uncontrolled Keywords: Nanocarrier, Sustained release, Inhibitor, Glaucoma, Fibrosis
Subjects: Q Science > QH Natural history > QH301 Biology
Divisions: Biology
Date Deposited: 04 Feb 2019 15:48
URI: http://repository.edgehill.ac.uk/id/eprint/11009

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