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http://digitalrepository.fccollege.edu.pk/handle/123456789/1241
Title: | Lipodendriplexes mediated enhanced gene delivery: a cellular to pre‑clinical investigation |
Authors: | Tariq, Imran Ali, Muhammad Yasir Sohail, , Muhammad Farhan Amin, Muhammad Umair Ali, Sajid Bukhari, Nadeem Irfan Raza, Abida Pinnapireddy, Shashank Reddy Schäfer, Jens Bakowsky, Udo |
Keywords: | lipodendriplexes gene delivery cellular clinical investigation |
Issue Date: | 8-Dec-2020 |
Publisher: | Pubmed |
Citation: | Tariq I, Ali MY, Sohail MF, Amin MU, Ali S, Bukhari NI, Raza A, Pinnapireddy SR, Schäfer J, Bakowsky U. Lipodendriplexes mediated enhanced gene delivery: a cellular to pre-clinical investigation. Sci Rep. 2020 Dec 8;10(1):21446. doi: 10.1038/s41598-020-78123-6. PMID: 33293580; PMCID: PMC7723038. |
Series/Report no.: | Sci Rep . 2020 Dec 8;10(1):21446.; |
Abstract: | Clinical success of efective gene therapy is mainly hampered by the insufciency of safe and efcient internalization of a transgene to the targeted cellular site. Therefore, the development of a safe and efcient nanocarrier system is one of the fundamental challenges to transfer the therapeutic genes to the diseased cells. Polyamidoamine (PAMAM) dendrimer has been used as an efcient non-viral gene vector (dendriplexes) but the toxicity and unusual biodistribution induced by the terminal amino groups (–NH2) limit its in vivo applications. Hence, a state of the art lipid modifcation with PAMAM based gene carrier (lipodendriplexes) was planned to investigate theirs in vitro (2D and 3D cell culture) and in vivo behaviour. In vitro pDNA transfection, lactate dehydrogenase (LDH) release, reactive oxygen species (ROS) generation, cellular protein contents, live/dead staining and apoptosis were studied in 2D cell culture of HEK-293 cells while GFP transfection, 3D cell viability and live/ dead staining of spheroids were performed in its 3D cell culture. Acute toxicity studies including organ to body index ratio, hematological parameters, serum biochemistry, histopathological profles and in vivo transgene expression were assessed in female BALB/c mice. The results suggested that, in comparison to dendriplexes the lipodendriplexes exhibited signifcant improvement of pDNA transfection (p< 0.001) with lower LDH release (p< 0.01) and ROS generation (p< 0.05). A substantially higher cellular protein content (p< 0.01) and cell viability were also observed in 2D culture. A strong GFP expression with an improved cell viability profle (p< 0.05) was indicated in lipodendriplexes treated 3D spheroids. In vivo archives showed the superiority of lipid-modifed nanocarrier system, depicted a signifcant increase in green fuorescent protein (GFP) expression in the lungs (p< 0.01), heart (p< 0.001), liver (p< 0.001) and kidneys (p< 0.001) with improved serum biochemistry and hematological profle as compared to unmodifed dendriplexes. No tissue necrosis was evident in the animal groups treated with lipid-shielded molecules. Therefore, a non-covalent conjugation of lipids with PAMAM based carrier system could be considered as a promising approach for an efcient and biocompatible gene delivery system. |
Description: | https://pubmed.ncbi.nlm.nih.gov/33293580/ |
URI: | http://localhost:8080/xmlui/handle/123456789/1241 |
Appears in Collections: | Pharmacy Department |
Files in This Item:
File | Description | Size | Format | |
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Lipodendriplexes mediated enhanced gene delivery; a cellular to pre-clinical investigation.pdf | 10.2 MB | Adobe PDF | View/Open |
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