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

Aristides Tagalakis, Shivam Madaan, Scott D. Larsen, Richard R. Neubig, Peng T. Khaw, Cynthia Yu-Wai-Man

Research output: Contribution to journalArticle

2 Citations (Scopus)
4 Downloads (Pure)

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.
Original languageEnglish
JournalJournal of Nanobiotechnology
Volume16
Issue number97
Early online date27 Nov 2018
DOIs
Publication statusE-pub ahead of print - 27 Nov 2018

Fingerprint

Serum Response Factor
Transcription factors
Glaucoma
Filtering Surgery
Surgery
Fibrosis
Transcription Factors
Unilamellar Liposomes
Propane
Liposomes
High performance liquid chromatography
Fibroblasts
Drug delivery
Gene expression
Rabbits
Blister
Cicatrix
High Pressure Liquid Chromatography
Gene Expression
Survival

Keywords

  • Nanocarrier
  • Sustained release
  • Inhibitor
  • Glaucoma
  • Fibrosis

Cite this

Tagalakis, Aristides ; Madaan, Shivam ; Larsen, Scott D. ; Neubig, Richard R. ; Khaw, Peng T. ; Yu-Wai-Man, Cynthia. / In vitro and in vivo delivery of a sustained release nanocarrier-based formulation of an MRTF/SRF inhibitor in conjunctival fibrosis. In: Journal of Nanobiotechnology. 2018 ; Vol. 16, No. 97.
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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.",
keywords = "Nanocarrier, Sustained release, Inhibitor, Glaucoma, Fibrosis",
author = "Aristides Tagalakis and Shivam Madaan and Larsen, {Scott D.} and Neubig, {Richard R.} and Khaw, {Peng T.} and Cynthia Yu-Wai-Man",
note = "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.",
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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.; Yu-Wai-Man, Cynthia.

In: Journal of Nanobiotechnology, Vol. 16, No. 97, 27.11.2018.

Research output: Contribution to journalArticle

TY - JOUR

T1 - In vitro and in vivo delivery of a sustained release nanocarrier-based formulation of an MRTF/SRF inhibitor in conjunctival fibrosis

AU - Tagalakis, Aristides

AU - Madaan, Shivam

AU - Larsen, Scott D.

AU - Neubig, Richard R.

AU - Khaw, Peng T.

AU - Yu-Wai-Man, Cynthia

N1 - 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.

PY - 2018/11/27

Y1 - 2018/11/27

N2 - 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.

AB - 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.

KW - Nanocarrier

KW - Sustained release

KW - Inhibitor

KW - Glaucoma

KW - Fibrosis

U2 - 10.1186/s12951-018-0425-3

DO - 10.1186/s12951-018-0425-3

M3 - Article

VL - 16

JO - Journal of Nanobiotechnology

JF - Journal of Nanobiotechnology

SN - 1477-3155

IS - 97

ER -