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

BACKGROUND: Sustained drug delivery is a large 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

Fracture criterion and mathematical conjectures from fracture mechanics

This paper is written to state mathematical problems which are proved or not proved. Here the term 'proved' means the conjectures hold for weak solutions. These conjecture are already confirmed using special solutions. In fracture mechanics, it will be enough. But the weak solution cover all cases, which give the standard in fracture mechanics. The aim of this paper is to state the historical results in fracture mechanics and to give the conjectures which will be proved (or improved or extended) in later by functional analysis. Because of a singularity of elastic field at crack front, special care should be taken in applying the classical mechanical results. There are huge research on fracture phenomenon, then we cannot state all of them. Mainly, we state here the classical results of brittle fracture which most fracture engineer will agree nearly true. It is impossible to construct one theory which express fracture phenomenon, because the experiment point out that fracture phenomenon is different for materials and in conditions. In general, the results in engineering will not clear from mathematical view-point. There are many conjectures and hypothesis from fracture mechanics that are slightly changed from original papers. (orig.)Available from TIB Hannover: RR 6943(96-18) / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekSIGLEDEGerman