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Limiting the level of tertiary amines on polyamines leads to biocompatible nucleic acid vectors

Simão Carlos, MI; Zheng, K; Garrett, N; Arifin, N; Workman, DG; Kubajewska, I; Halwani, AA; ... Uchegbu, IF; + view all (2017) Limiting the level of tertiary amines on polyamines leads to biocompatible nucleic acid vectors. International Journal of Pharmaceutics , 526 (1-2) pp. 106-125. 10.1016/j.ijpharm.2017.04.059. Green open access

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Abstract

We have designed an efficient, synthetic nucleic acid vector, which is relatively non-toxic. [N-(2-ethylamino)-6-O-glycolchitosan - EAGC] polymers were 10 - 50 fold less toxic than Lipofectamine 2000, able to complex DNA, mRNA and siRNA into positively charged (zeta potential=+40 - 50mV), 50-450nm nanoparticles. The level of tertiary amine N-2-ethylamino substitution (DStert) was inversely proportional to the IC50 of the EAGC polymers in the A431 cell line: IC50=6.18DStert(-0.9), r(2)=0.9991. EAGC polyplexes were stable against a heparin challenge, able to protect the nucleic acids from nuclease degradation and achieve levels of transfection comparable to Lipofectamine 2000 formulations. The relative biocompatibility of the vector allowed 10 fold higher doses of DNA (1μg compared to 0.1μg per well with Lipofectamine 2000) and siRNA (10.7μg per well vs 1.3μg with Lipofectamine 2000) to be applied to cells, when compared to Lipofectamine 2000. Finally intranasal application of EAGC - siRNA complexes resulted in siRNA transfer to the neurons of the olfactory bulb.

Type: Article
Title: Limiting the level of tertiary amines on polyamines leads to biocompatible nucleic acid vectors
Location: Netherlands
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.ijpharm.2017.04.059
Publisher version: http://doi.org/10.1016/j.ijpharm.2017.04.059
Language: English
Additional information: © 2017 Elsevier B.V. All rights reserved. This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: Chitosan, DNA, Gene Therapy, N-(2-ethylamino)-6-O-glycolchitosan, Nucleic acid delivery, Polymer, mRNA, siRNA
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
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
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy > Pharma and Bio Chemistry
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy > Pharmaceutics
URI: https://discovery.ucl.ac.uk/id/eprint/1554524
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