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Multifunctional PEG Retinylamine Conjugate Provides Prolonged Protection against Retinal Degeneration in Mice

[Image: see text] A polyethylene glycol (PEG) retinylamine (Ret-NH(2)) conjugate PEG-GFL-NH-Ret with a glycine-phenylalanine-leucine (GFL) spacer was synthesized for controlled oral delivery of Ret-NH(2) to treat retinal degenerative diseases, including Stargardt disease (STGD) and age-related macul...

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Autores principales: Yu, Guanping, Wu, Xueming, Ayat, Nadia, Maeda, Akiko, Gao, Song-Qi, Golczak, Marcin, Palczewski, Krzysztof, Lu, Zheng-Rong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2014
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4261990/
https://www.ncbi.nlm.nih.gov/pubmed/25390360
http://dx.doi.org/10.1021/bm501352s
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author Yu, Guanping
Wu, Xueming
Ayat, Nadia
Maeda, Akiko
Gao, Song-Qi
Golczak, Marcin
Palczewski, Krzysztof
Lu, Zheng-Rong
author_facet Yu, Guanping
Wu, Xueming
Ayat, Nadia
Maeda, Akiko
Gao, Song-Qi
Golczak, Marcin
Palczewski, Krzysztof
Lu, Zheng-Rong
author_sort Yu, Guanping
collection PubMed
description [Image: see text] A polyethylene glycol (PEG) retinylamine (Ret-NH(2)) conjugate PEG-GFL-NH-Ret with a glycine-phenylalanine-leucine (GFL) spacer was synthesized for controlled oral delivery of Ret-NH(2) to treat retinal degenerative diseases, including Stargardt disease (STGD) and age-related macular degeneration (AMD). The peptide spacer was introduced for sustained release of the drug by digestive enzymes in the gastrointestinal tract. The pharmacokinetics experiments showed that the PEG conjugate could control the sustained drug release after oral administration and had much lower nonspecific liver drug accumulation than the free drug in wild-type female C57BL mice. In the mean time, the conjugate maintained the same concentration of Ret-NH(2) in the eye as the free drug. Also, PEG-GFL-NH-Ret at a Ret-NH(2) equivalent dose of 25 mg/kg produced complete protection of Abca4(–/–)Rdh8(–/–) mouse retinas against light-induced retinal degeneration for 3 days after oral administration, as revealed by OCT retina imaging, whereas free Ret-NH(2) did not provide any protection under identical conditions. The polymer conjugate PEG-GFL-NH-Ret has great potential for controlled delivery of Ret-NH(2) to the eye for effective protection against retinal degenerative diseases.
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spelling pubmed-42619902015-11-12 Multifunctional PEG Retinylamine Conjugate Provides Prolonged Protection against Retinal Degeneration in Mice Yu, Guanping Wu, Xueming Ayat, Nadia Maeda, Akiko Gao, Song-Qi Golczak, Marcin Palczewski, Krzysztof Lu, Zheng-Rong Biomacromolecules [Image: see text] A polyethylene glycol (PEG) retinylamine (Ret-NH(2)) conjugate PEG-GFL-NH-Ret with a glycine-phenylalanine-leucine (GFL) spacer was synthesized for controlled oral delivery of Ret-NH(2) to treat retinal degenerative diseases, including Stargardt disease (STGD) and age-related macular degeneration (AMD). The peptide spacer was introduced for sustained release of the drug by digestive enzymes in the gastrointestinal tract. The pharmacokinetics experiments showed that the PEG conjugate could control the sustained drug release after oral administration and had much lower nonspecific liver drug accumulation than the free drug in wild-type female C57BL mice. In the mean time, the conjugate maintained the same concentration of Ret-NH(2) in the eye as the free drug. Also, PEG-GFL-NH-Ret at a Ret-NH(2) equivalent dose of 25 mg/kg produced complete protection of Abca4(–/–)Rdh8(–/–) mouse retinas against light-induced retinal degeneration for 3 days after oral administration, as revealed by OCT retina imaging, whereas free Ret-NH(2) did not provide any protection under identical conditions. The polymer conjugate PEG-GFL-NH-Ret has great potential for controlled delivery of Ret-NH(2) to the eye for effective protection against retinal degenerative diseases. American Chemical Society 2014-11-12 2014-12-08 /pmc/articles/PMC4261990/ /pubmed/25390360 http://dx.doi.org/10.1021/bm501352s Text en Copyright © 2014 American Chemical Society This is an open access article published under an ACS AuthorChoice License (http://pubs.acs.org/page/policy/authorchoice_termsofuse.html) , which permits copying and redistribution of the article or any adaptations for non-commercial purposes.
spellingShingle Yu, Guanping
Wu, Xueming
Ayat, Nadia
Maeda, Akiko
Gao, Song-Qi
Golczak, Marcin
Palczewski, Krzysztof
Lu, Zheng-Rong
Multifunctional PEG Retinylamine Conjugate Provides Prolonged Protection against Retinal Degeneration in Mice
title Multifunctional PEG Retinylamine Conjugate Provides Prolonged Protection against Retinal Degeneration in Mice
title_full Multifunctional PEG Retinylamine Conjugate Provides Prolonged Protection against Retinal Degeneration in Mice
title_fullStr Multifunctional PEG Retinylamine Conjugate Provides Prolonged Protection against Retinal Degeneration in Mice
title_full_unstemmed Multifunctional PEG Retinylamine Conjugate Provides Prolonged Protection against Retinal Degeneration in Mice
title_short Multifunctional PEG Retinylamine Conjugate Provides Prolonged Protection against Retinal Degeneration in Mice
title_sort multifunctional peg retinylamine conjugate provides prolonged protection against retinal degeneration in mice
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4261990/
https://www.ncbi.nlm.nih.gov/pubmed/25390360
http://dx.doi.org/10.1021/bm501352s
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