Systemic in vivo delivery of siRNA to tumours using combination of polyethyleneimine and transferrin–polyethyleneimine conjugates

Materials for delivery of oligonucleotides need to be simple to produce yet effective in vivo to be considered for clinical applications. Formulations of biomaterials based on combinations of existing demonstrated polymeric gene carriers with targeted derivatives are potential candidates for rapid t...

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Main Authors:	Grabowska, Anna M., Kircheis, Ralf, Kumari, Rajendra, Clarke, Philip, McKenzie, Andrew, Hughes, Jaime, Mayne, Cerys, Desai, Arpan, Sasso, Luana, Watson, Susan A., Alexander, Cameron
Format:	Article
Language:	English
Published:	Royal Society of Chemistry 2015
Online Access:	http://eprints.nottingham.ac.uk/39081/ http://eprints.nottingham.ac.uk/39081/ http://eprints.nottingham.ac.uk/39081/ http://eprints.nottingham.ac.uk/39081/1/Grabowska%20systemic.pdf

id	nottingham-39081
recordtype	eprints
spelling	nottingham-390812018-07-02T09:09:45Z http://eprints.nottingham.ac.uk/39081/ Systemic in vivo delivery of siRNA to tumours using combination of polyethyleneimine and transferrin–polyethyleneimine conjugates Grabowska, Anna M. Kircheis, Ralf Kumari, Rajendra Clarke, Philip McKenzie, Andrew Hughes, Jaime Mayne, Cerys Desai, Arpan Sasso, Luana Watson, Susan A. Alexander, Cameron Materials for delivery of oligonucleotides need to be simple to produce yet effective in vivo to be considered for clinical applications. Formulations of biomaterials based on combinations of existing demonstrated polymeric gene carriers with targeted derivatives are potential candidates for rapid translation but have not been fully explored for siRNA applications. Here we investigated formulations based on derivatised PEI for delivery of siRNA to gastrointestinal cancer cells. siRNA was complexed with linear PEI alone or with a mixture of linear PEI and transferrin-conjugated branched PEI (TfPEI), and knockdown of reporter genes was investigated. Overall, the in vitro use of complexes containing TfPEI resulted in up to 93% knockdown at 72 h post-transfection. Sustained knockdown was also achieved in a bioluminescent xenograft model. When complexes were delivered intratumorally, a 43% reduction in luminescence was achieved in the treated group compared with the control group 48 h after treatment. For systemic administration, only the intraperitoneal route, and not the intravenous route was effective, with 49% knockdown achieved at 72 h and sustained up to 144 h (44%) after a single administration of TfPEI-complexed siRNA. No toxicity or induction of the interferon response was observed. These findings demonstrate that simple formulations of transferrin-conjugated PEI with a ‘parent’ polymer such as linear PEI have potential as a method for therapeutic delivery of siRNA when administered either intratumorally or systemically. Royal Society of Chemistry 2015-11-01 Article PeerReviewed application/pdf en cc_by http://eprints.nottingham.ac.uk/39081/1/Grabowska%20systemic.pdf Grabowska, Anna M. and Kircheis, Ralf and Kumari, Rajendra and Clarke, Philip and McKenzie, Andrew and Hughes, Jaime and Mayne, Cerys and Desai, Arpan and Sasso, Luana and Watson, Susan A. and Alexander, Cameron (2015) Systemic in vivo delivery of siRNA to tumours using combination of polyethyleneimine and transferrin–polyethyleneimine conjugates. Biomaterials Science, 3 (11). pp. 1439-1448. ISSN 2047-4830 http://dx.doi.org/10.1039/C5BM00101C doi:10.1039/C5BM00101C doi:10.1039/C5BM00101C
repository_type	Digital Repository
institution_category	Local University
institution	University of Nottingham Malaysia Campus
building	Nottingham Research Data Repository
collection	Online Access
language	English
description	Materials for delivery of oligonucleotides need to be simple to produce yet effective in vivo to be considered for clinical applications. Formulations of biomaterials based on combinations of existing demonstrated polymeric gene carriers with targeted derivatives are potential candidates for rapid translation but have not been fully explored for siRNA applications. Here we investigated formulations based on derivatised PEI for delivery of siRNA to gastrointestinal cancer cells. siRNA was complexed with linear PEI alone or with a mixture of linear PEI and transferrin-conjugated branched PEI (TfPEI), and knockdown of reporter genes was investigated. Overall, the in vitro use of complexes containing TfPEI resulted in up to 93% knockdown at 72 h post-transfection. Sustained knockdown was also achieved in a bioluminescent xenograft model. When complexes were delivered intratumorally, a 43% reduction in luminescence was achieved in the treated group compared with the control group 48 h after treatment. For systemic administration, only the intraperitoneal route, and not the intravenous route was effective, with 49% knockdown achieved at 72 h and sustained up to 144 h (44%) after a single administration of TfPEI-complexed siRNA. No toxicity or induction of the interferon response was observed. These findings demonstrate that simple formulations of transferrin-conjugated PEI with a ‘parent’ polymer such as linear PEI have potential as a method for therapeutic delivery of siRNA when administered either intratumorally or systemically.
format	Article
author	Grabowska, Anna M. Kircheis, Ralf Kumari, Rajendra Clarke, Philip McKenzie, Andrew Hughes, Jaime Mayne, Cerys Desai, Arpan Sasso, Luana Watson, Susan A. Alexander, Cameron
spellingShingle	Grabowska, Anna M. Kircheis, Ralf Kumari, Rajendra Clarke, Philip McKenzie, Andrew Hughes, Jaime Mayne, Cerys Desai, Arpan Sasso, Luana Watson, Susan A. Alexander, Cameron Systemic in vivo delivery of siRNA to tumours using combination of polyethyleneimine and transferrin–polyethyleneimine conjugates
author_facet	Grabowska, Anna M. Kircheis, Ralf Kumari, Rajendra Clarke, Philip McKenzie, Andrew Hughes, Jaime Mayne, Cerys Desai, Arpan Sasso, Luana Watson, Susan A. Alexander, Cameron
author_sort	Grabowska, Anna M.
title	Systemic in vivo delivery of siRNA to tumours using combination of polyethyleneimine and transferrin–polyethyleneimine conjugates
title_short	Systemic in vivo delivery of siRNA to tumours using combination of polyethyleneimine and transferrin–polyethyleneimine conjugates
title_full	Systemic in vivo delivery of siRNA to tumours using combination of polyethyleneimine and transferrin–polyethyleneimine conjugates
title_fullStr	Systemic in vivo delivery of siRNA to tumours using combination of polyethyleneimine and transferrin–polyethyleneimine conjugates
title_full_unstemmed	Systemic in vivo delivery of siRNA to tumours using combination of polyethyleneimine and transferrin–polyethyleneimine conjugates
title_sort	systemic in vivo delivery of sirna to tumours using combination of polyethyleneimine and transferrin–polyethyleneimine conjugates
publisher	Royal Society of Chemistry
publishDate	2015
url	http://eprints.nottingham.ac.uk/39081/ http://eprints.nottingham.ac.uk/39081/ http://eprints.nottingham.ac.uk/39081/ http://eprints.nottingham.ac.uk/39081/1/Grabowska%20systemic.pdf
first_indexed	2018-09-06T12:56:45Z
last_indexed	2018-09-06T12:56:45Z
_version_	1610862932570144768

Systemic in vivo delivery of siRNA to tumours using combination of polyethyleneimine and transferrin–polyethyleneimine conjugates

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