Alamoudi, Abdullah A;
Méndez, Paula A;
Workman, David;
Schätzlein, Andreas G;
Uchegbu, Ijeoma F;
(2022)
Brain Gene Silencing with Cationic Amino-Capped Poly(ethylene glycol) Polyplexes.
Biomedicines
, 10
(9)
, Article 2182. 10.3390/biomedicines10092182.
Preview |
PDF
Uchegbu_Brain Gene Silencing with Cationic Amino-Capped Poly(ethylene glycol) Polyplexes_VoR.pdf - Published Version Download (1MB) | Preview |
Abstract
Therapeutic gene silencing in the brain is usually achieved using highly invasive intracranial administration methods and/or comparatively toxic vectors. In this work, we use a relatively biocompatible vector: poly(ethylene glycol) star-shaped polymer capped with amine groups (4APPA) via the nose to brain route. 4APPA complexes anti- itchy E3 ubiquitin protein ligase (anti-ITCH) siRNA to form positively charged (zeta potential +15 ± 5 mV) 150 nm nanoparticles. The siRNA-4APPA polyplexes demonstrated low cellular toxicity (IC50 = 13.92 ± 6 mg mL−1) in the A431 cell line and were three orders of magnitude less toxic than Lipofectamine 2000 (IC50 = 0.033 ± 0.04 mg mL−1) in this cell line. Cell association and uptake of fluorescently labelled siRNA bound to siRNA-4APPA nanoparticles was demonstrated using fluorescent activated cell sorting (FACS) and confocal laser scanning microscopy (CLSM), respectively. Gene silencing of the ITCH gene was observed in vitro in the A431 cell line (65% down regulation when compared to the use of anti-ITCH siRNA alone). On intranasal dosing with fluorescently labelled siRNA-4APPA polyplexes, fluorescence was seen in the cells of the olfactory bulb, cerebral cortex and mid-brain regions. Finally, down regulation of ITCH was seen in the brain cells (54 ± 13% ITCH remaining compared to untreated controls) in a healthy rat model, following intranasal dosing of siRNA-4APPA nanoparticles (0.15 mg kg−1 siRNA twice daily for 3 days). Gene silencing in the brain may be achieved by intranasal administration of siRNA- poly(ethylene glycol) based polyplexes.
| Type: | Article |
|---|---|
| Title: | Brain Gene Silencing with Cationic Amino-Capped Poly(ethylene glycol) Polyplexes |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.3390/biomedicines10092182 |
| Publisher version: | https://doi.org/10.3390/biomedicines10092182 |
| Language: | English |
| Additional information: | © 2022 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 (https:// creativecommons.org/licenses/by/ 4.0/). |
| Keywords: | siRNA delivery; brain; gene silencing; polyethylene glycol (PEG); nanoparticles; intranasal |
| UCL classification: | UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy > Pharmaceutics UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy > Pharma and Bio Chemistry |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10155959 |
Archive Staff Only
 |
View Item |
