A novel disulfide bond-mediated cleavable RGD-modified PAMAM nanocomplex containing nuclear localization signal HMGB1 for enhancing gene transfection efficiency

Ji Li, Yuting Han, Yue Lu, Baohui Song, Ming Zhao, Haiyang Hu, Dawei Chen Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, Shenyang 110016, China Background: Polyamidoamine (PAMAM) dendrimers modified by polyethylene glycol (PEG) have frequently been investigate...

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Autores principales:	Li J, Han Y, Lu Y, Song B, Zhao M, Hu H, Chen D
Formato:	article
Lenguaje:	EN
Publicado:	Dove Medical Press 2018
Materias:	PAMAM dendrimers disulfide bond RGD HMGB1 gene delivery Medicine (General) R5-920
Acceso en línea:	https://doaj.org/article/debff57a4d1d4b01981026ed09cb3b16
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spelling	oai:doaj.org-article:debff57a4d1d4b01981026ed09cb3b162021-12-02T00:13:14ZA novel disulfide bond-mediated cleavable RGD-modified PAMAM nanocomplex containing nuclear localization signal HMGB1 for enhancing gene transfection efficiency1178-2013https://doaj.org/article/debff57a4d1d4b01981026ed09cb3b162018-11-01T00:00:00Zhttps://www.dovepress.com/a-novel-disulfide-bond-mediated-cleavable-rgd-modified-pamam-nanocompl-peer-reviewed-article-IJNhttps://doaj.org/toc/1178-2013Ji Li, Yuting Han, Yue Lu, Baohui Song, Ming Zhao, Haiyang Hu, Dawei Chen Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, Shenyang 110016, China Background: Polyamidoamine (PAMAM) dendrimers modified by polyethylene glycol (PEG) have frequently been investigated as a delivery carrier for gene therapy. However, modification of PAMAM with PEG using covalent linkage significantly reduces the cellular uptake rate and the transfection efficiency. How to conquer these barriers becomes a burning question in gene delivery. Materials and methods: The present study constructed an effective disulfide bond-mediated cleavable RGD modified gene delivery system to overcome the aforementioned limitations. The disulfide bond was introduced between PAMAM dendrimers and PEG chains to realize the cleavage of PEG from the carrier system, whereas the arginine-glycine-aspartate (RGD) peptide was expected to promote the cellular uptake rate. A high mobility group Box 1 (HMGB1) protein containing nuclear localization signal (NLS) was simultaneously introduced to further promote gene expression efficiency. A pDNA/HMGB1/PAMAM-SS-PEG-RGD (DHP) nanocomplex was prepared via electrostatic interaction and characterized. Results: The results showed that DHP generated small particles and was able to condense and protect pDNA against degradation. In addition, the RGD peptide could significantly promote the cellular uptake of a nanocomplex. Intracellular trafficking and in vitro expression study indicated that the DHP nanocomplex escaped from lysosomes and the disulfide bonds between PAMAM and PEG cleaved due to the high concentration of GSH in the cytoplasm, pDNA consequently became exclusively located in the nucleus under the guidance of HMGB1, thereby promoting the red fluorescence protein (RFP) expression. Importantly, an in vivo antitumor activity study demonstrated that the DHP nanocomplex had higher antitumor activity than any other reference preparation. Conclusion: All these results confirm that DHP could be a new strategy for improving the transfection and expression efficiency in gene delivery. Keywords: PAMAM dendrimers, disulfide bond, RGD, HMGB1, gene deliveryLi JHan YLu YSong BZhao MHu HChen DDove Medical PressarticlePAMAM dendrimersdisulfide bondRGDHMGB1gene deliveryMedicine (General)R5-920ENInternational Journal of Nanomedicine, Vol Volume 13, Pp 7135-7153 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	PAMAM dendrimers disulfide bond RGD HMGB1 gene delivery Medicine (General) R5-920
spellingShingle	PAMAM dendrimers disulfide bond RGD HMGB1 gene delivery Medicine (General) R5-920 Li J Han Y Lu Y Song B Zhao M Hu H Chen D A novel disulfide bond-mediated cleavable RGD-modified PAMAM nanocomplex containing nuclear localization signal HMGB1 for enhancing gene transfection efficiency
description	Ji Li, Yuting Han, Yue Lu, Baohui Song, Ming Zhao, Haiyang Hu, Dawei Chen Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, Shenyang 110016, China Background: Polyamidoamine (PAMAM) dendrimers modified by polyethylene glycol (PEG) have frequently been investigated as a delivery carrier for gene therapy. However, modification of PAMAM with PEG using covalent linkage significantly reduces the cellular uptake rate and the transfection efficiency. How to conquer these barriers becomes a burning question in gene delivery. Materials and methods: The present study constructed an effective disulfide bond-mediated cleavable RGD modified gene delivery system to overcome the aforementioned limitations. The disulfide bond was introduced between PAMAM dendrimers and PEG chains to realize the cleavage of PEG from the carrier system, whereas the arginine-glycine-aspartate (RGD) peptide was expected to promote the cellular uptake rate. A high mobility group Box 1 (HMGB1) protein containing nuclear localization signal (NLS) was simultaneously introduced to further promote gene expression efficiency. A pDNA/HMGB1/PAMAM-SS-PEG-RGD (DHP) nanocomplex was prepared via electrostatic interaction and characterized. Results: The results showed that DHP generated small particles and was able to condense and protect pDNA against degradation. In addition, the RGD peptide could significantly promote the cellular uptake of a nanocomplex. Intracellular trafficking and in vitro expression study indicated that the DHP nanocomplex escaped from lysosomes and the disulfide bonds between PAMAM and PEG cleaved due to the high concentration of GSH in the cytoplasm, pDNA consequently became exclusively located in the nucleus under the guidance of HMGB1, thereby promoting the red fluorescence protein (RFP) expression. Importantly, an in vivo antitumor activity study demonstrated that the DHP nanocomplex had higher antitumor activity than any other reference preparation. Conclusion: All these results confirm that DHP could be a new strategy for improving the transfection and expression efficiency in gene delivery. Keywords: PAMAM dendrimers, disulfide bond, RGD, HMGB1, gene delivery
format	article
author	Li J Han Y Lu Y Song B Zhao M Hu H Chen D
author_facet	Li J Han Y Lu Y Song B Zhao M Hu H Chen D
author_sort	Li J
title	A novel disulfide bond-mediated cleavable RGD-modified PAMAM nanocomplex containing nuclear localization signal HMGB1 for enhancing gene transfection efficiency
title_short	A novel disulfide bond-mediated cleavable RGD-modified PAMAM nanocomplex containing nuclear localization signal HMGB1 for enhancing gene transfection efficiency
title_full	A novel disulfide bond-mediated cleavable RGD-modified PAMAM nanocomplex containing nuclear localization signal HMGB1 for enhancing gene transfection efficiency
title_fullStr	A novel disulfide bond-mediated cleavable RGD-modified PAMAM nanocomplex containing nuclear localization signal HMGB1 for enhancing gene transfection efficiency
title_full_unstemmed	A novel disulfide bond-mediated cleavable RGD-modified PAMAM nanocomplex containing nuclear localization signal HMGB1 for enhancing gene transfection efficiency
title_sort	novel disulfide bond-mediated cleavable rgd-modified pamam nanocomplex containing nuclear localization signal hmgb1 for enhancing gene transfection efficiency
publisher	Dove Medical Press
publishDate	2018
url	https://doaj.org/article/debff57a4d1d4b01981026ed09cb3b16
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A novel disulfide bond-mediated cleavable RGD-modified PAMAM nanocomplex containing nuclear localization signal HMGB1 for enhancing gene transfection efficiency

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