Cargando…

In Situ Gel Incorporating Disulfiram Nanoparticles Rescues the Retinal Dysfunction via ATP Collapse in Otsuka Long–Evans Tokushima Fatty Rats

We attempted to design an ophthalmic in situ gel formulation incorporating disulfiram (DIS) nanoparticles (Dis-NPs/ISG) and demonstrated the therapeutic effect of Dis-NPs/ISG on retinal dysfunction in 15-month-old Otsuka Long–Evans Tokushima Fatty (OLETF) rats, a rat model of diabetes. The DIS parti...

Descripción completa

Detalles Bibliográficos
Autores principales: Deguchi, Saori, Ogata, Fumihiko, Yamaguchi, Mizuki, Minami, Misa, Otake, Hiroko, Kanai, Kazutaka, Kawasaki, Naohito, Nagai, Noriaki
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7601925/
https://www.ncbi.nlm.nih.gov/pubmed/32993012
http://dx.doi.org/10.3390/cells9102171
_version_ 1783603548798320640
author Deguchi, Saori
Ogata, Fumihiko
Yamaguchi, Mizuki
Minami, Misa
Otake, Hiroko
Kanai, Kazutaka
Kawasaki, Naohito
Nagai, Noriaki
author_facet Deguchi, Saori
Ogata, Fumihiko
Yamaguchi, Mizuki
Minami, Misa
Otake, Hiroko
Kanai, Kazutaka
Kawasaki, Naohito
Nagai, Noriaki
author_sort Deguchi, Saori
collection PubMed
description We attempted to design an ophthalmic in situ gel formulation incorporating disulfiram (DIS) nanoparticles (Dis-NPs/ISG) and demonstrated the therapeutic effect of Dis-NPs/ISG on retinal dysfunction in 15-month-old Otsuka Long–Evans Tokushima Fatty (OLETF) rats, a rat model of diabetes. The DIS particles were crushed using a bead mill to prepare the nanoparticles, and the Dis-NPs/ISG was prepared using a combination of the DIS nanoparticles and an in situ gelling system based on methylcellulose (MC). The particle size of the Dis-NPs/ISG was 80–250 nm, and there was no detectable precipitation or aggregation for 1 month. Moreover, the Dis-NPs/ISG was gelled at 37 °C, and the drug was delivered into the retina by instillation. Only diethyldithiocarbamate (DDC) was detected in the retina (DIS was not detected) when the Dis-NPs/ISG was instilled in the right eye, and the DDC levels in the right retina were significantly higher than those in the left retina. In addition, the retinal residence time of the drug was prolonged by the application of the in situ gelling system, since the DDC levels in the retinas of rats instilled with Dis-NPs/ISG were higher than those in DIS nanoparticles without MC. Furthermore, repetitive instillation of the Dis-NPs/ISG attenuated the deterioration of electroretinograms (ERGs) in 15-month-old OLETF rats by preventing the collapse of ATP production via excessive nitric oxide and recovered the decrease in retinal function. These findings provide important information for the development of novel therapeutic approaches to diabetic retinopathy.
format Online
Article
Text
id pubmed-7601925
institution National Center for Biotechnology Information
language English
publishDate 2020
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-76019252020-11-01 In Situ Gel Incorporating Disulfiram Nanoparticles Rescues the Retinal Dysfunction via ATP Collapse in Otsuka Long–Evans Tokushima Fatty Rats Deguchi, Saori Ogata, Fumihiko Yamaguchi, Mizuki Minami, Misa Otake, Hiroko Kanai, Kazutaka Kawasaki, Naohito Nagai, Noriaki Cells Article We attempted to design an ophthalmic in situ gel formulation incorporating disulfiram (DIS) nanoparticles (Dis-NPs/ISG) and demonstrated the therapeutic effect of Dis-NPs/ISG on retinal dysfunction in 15-month-old Otsuka Long–Evans Tokushima Fatty (OLETF) rats, a rat model of diabetes. The DIS particles were crushed using a bead mill to prepare the nanoparticles, and the Dis-NPs/ISG was prepared using a combination of the DIS nanoparticles and an in situ gelling system based on methylcellulose (MC). The particle size of the Dis-NPs/ISG was 80–250 nm, and there was no detectable precipitation or aggregation for 1 month. Moreover, the Dis-NPs/ISG was gelled at 37 °C, and the drug was delivered into the retina by instillation. Only diethyldithiocarbamate (DDC) was detected in the retina (DIS was not detected) when the Dis-NPs/ISG was instilled in the right eye, and the DDC levels in the right retina were significantly higher than those in the left retina. In addition, the retinal residence time of the drug was prolonged by the application of the in situ gelling system, since the DDC levels in the retinas of rats instilled with Dis-NPs/ISG were higher than those in DIS nanoparticles without MC. Furthermore, repetitive instillation of the Dis-NPs/ISG attenuated the deterioration of electroretinograms (ERGs) in 15-month-old OLETF rats by preventing the collapse of ATP production via excessive nitric oxide and recovered the decrease in retinal function. These findings provide important information for the development of novel therapeutic approaches to diabetic retinopathy. MDPI 2020-09-25 /pmc/articles/PMC7601925/ /pubmed/32993012 http://dx.doi.org/10.3390/cells9102171 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Deguchi, Saori
Ogata, Fumihiko
Yamaguchi, Mizuki
Minami, Misa
Otake, Hiroko
Kanai, Kazutaka
Kawasaki, Naohito
Nagai, Noriaki
In Situ Gel Incorporating Disulfiram Nanoparticles Rescues the Retinal Dysfunction via ATP Collapse in Otsuka Long–Evans Tokushima Fatty Rats
title In Situ Gel Incorporating Disulfiram Nanoparticles Rescues the Retinal Dysfunction via ATP Collapse in Otsuka Long–Evans Tokushima Fatty Rats
title_full In Situ Gel Incorporating Disulfiram Nanoparticles Rescues the Retinal Dysfunction via ATP Collapse in Otsuka Long–Evans Tokushima Fatty Rats
title_fullStr In Situ Gel Incorporating Disulfiram Nanoparticles Rescues the Retinal Dysfunction via ATP Collapse in Otsuka Long–Evans Tokushima Fatty Rats
title_full_unstemmed In Situ Gel Incorporating Disulfiram Nanoparticles Rescues the Retinal Dysfunction via ATP Collapse in Otsuka Long–Evans Tokushima Fatty Rats
title_short In Situ Gel Incorporating Disulfiram Nanoparticles Rescues the Retinal Dysfunction via ATP Collapse in Otsuka Long–Evans Tokushima Fatty Rats
title_sort in situ gel incorporating disulfiram nanoparticles rescues the retinal dysfunction via atp collapse in otsuka long–evans tokushima fatty rats
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7601925/
https://www.ncbi.nlm.nih.gov/pubmed/32993012
http://dx.doi.org/10.3390/cells9102171
work_keys_str_mv AT deguchisaori insitugelincorporatingdisulfiramnanoparticlesrescuestheretinaldysfunctionviaatpcollapseinotsukalongevanstokushimafattyrats
AT ogatafumihiko insitugelincorporatingdisulfiramnanoparticlesrescuestheretinaldysfunctionviaatpcollapseinotsukalongevanstokushimafattyrats
AT yamaguchimizuki insitugelincorporatingdisulfiramnanoparticlesrescuestheretinaldysfunctionviaatpcollapseinotsukalongevanstokushimafattyrats
AT minamimisa insitugelincorporatingdisulfiramnanoparticlesrescuestheretinaldysfunctionviaatpcollapseinotsukalongevanstokushimafattyrats
AT otakehiroko insitugelincorporatingdisulfiramnanoparticlesrescuestheretinaldysfunctionviaatpcollapseinotsukalongevanstokushimafattyrats
AT kanaikazutaka insitugelincorporatingdisulfiramnanoparticlesrescuestheretinaldysfunctionviaatpcollapseinotsukalongevanstokushimafattyrats
AT kawasakinaohito insitugelincorporatingdisulfiramnanoparticlesrescuestheretinaldysfunctionviaatpcollapseinotsukalongevanstokushimafattyrats
AT nagainoriaki insitugelincorporatingdisulfiramnanoparticlesrescuestheretinaldysfunctionviaatpcollapseinotsukalongevanstokushimafattyrats