Cargando…
Hydroxyethyl substituted linear polyethylenimine for safe and efficient delivery of siRNA therapeutics
Linear polyethylenimine (LPEI) has been well reported as a carrier for siRNA delivery. However, its applications are limited due to its highly ionized state at physiologic pH and the resultant charge mediated toxicity. The presence of ionizable secondary amines in LPE are responsible for its unique...
Autores principales: | , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
The Royal Society of Chemistry
2018
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9087824/ https://www.ncbi.nlm.nih.gov/pubmed/35547911 http://dx.doi.org/10.1039/c8ra06298f |
_version_ | 1784704236955631616 |
---|---|
author | Patil, Sushilkumar Lalani, Rohan Bhatt, Priyanka Vhora, Imran Patel, Vivek Patel, Hinal Misra, Ambikanandan |
author_facet | Patil, Sushilkumar Lalani, Rohan Bhatt, Priyanka Vhora, Imran Patel, Vivek Patel, Hinal Misra, Ambikanandan |
author_sort | Patil, Sushilkumar |
collection | PubMed |
description | Linear polyethylenimine (LPEI) has been well reported as a carrier for siRNA delivery. However, its applications are limited due to its highly ionized state at physiologic pH and the resultant charge mediated toxicity. The presence of ionizable secondary amines in LPE are responsible for its unique characteristics such as pH dependent solubility and positive charge. Therefore, modification of LPEI was carried out to obtain hydroxyethyl substituted LPEI with the degree of substitution ranging from 15% to 45%. The impact of modification on the physicochemical parameters of the polymer, i.e. buffer capacity, solubility, biocompatibility and stability, was evaluated. Surprisingly, despite the loss of ionizable amines, the substitution improved solubility, and even overcame the pH dependent solubility of LPEI. In addition, the conversion of secondary amines to less basic tertiary amines after substitution improved the buffer capacity, in the endosomal pH range, required for efficient endosomal escape. It also reduced erythrocyte aggregation, hemolytic potential and in vitro cytotoxicity. The in vitro studies showed enhanced cell uptake and mRNA knockdown efficiency. Thus, the proposed modification shows a simple approach to overcome the limitation of LPEI for siRNA delivery. |
format | Online Article Text |
id | pubmed-9087824 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | The Royal Society of Chemistry |
record_format | MEDLINE/PubMed |
spelling | pubmed-90878242022-05-10 Hydroxyethyl substituted linear polyethylenimine for safe and efficient delivery of siRNA therapeutics Patil, Sushilkumar Lalani, Rohan Bhatt, Priyanka Vhora, Imran Patel, Vivek Patel, Hinal Misra, Ambikanandan RSC Adv Chemistry Linear polyethylenimine (LPEI) has been well reported as a carrier for siRNA delivery. However, its applications are limited due to its highly ionized state at physiologic pH and the resultant charge mediated toxicity. The presence of ionizable secondary amines in LPE are responsible for its unique characteristics such as pH dependent solubility and positive charge. Therefore, modification of LPEI was carried out to obtain hydroxyethyl substituted LPEI with the degree of substitution ranging from 15% to 45%. The impact of modification on the physicochemical parameters of the polymer, i.e. buffer capacity, solubility, biocompatibility and stability, was evaluated. Surprisingly, despite the loss of ionizable amines, the substitution improved solubility, and even overcame the pH dependent solubility of LPEI. In addition, the conversion of secondary amines to less basic tertiary amines after substitution improved the buffer capacity, in the endosomal pH range, required for efficient endosomal escape. It also reduced erythrocyte aggregation, hemolytic potential and in vitro cytotoxicity. The in vitro studies showed enhanced cell uptake and mRNA knockdown efficiency. Thus, the proposed modification shows a simple approach to overcome the limitation of LPEI for siRNA delivery. The Royal Society of Chemistry 2018-10-16 /pmc/articles/PMC9087824/ /pubmed/35547911 http://dx.doi.org/10.1039/c8ra06298f Text en This journal is © The Royal Society of Chemistry https://creativecommons.org/licenses/by-nc/3.0/ |
spellingShingle | Chemistry Patil, Sushilkumar Lalani, Rohan Bhatt, Priyanka Vhora, Imran Patel, Vivek Patel, Hinal Misra, Ambikanandan Hydroxyethyl substituted linear polyethylenimine for safe and efficient delivery of siRNA therapeutics |
title | Hydroxyethyl substituted linear polyethylenimine for safe and efficient delivery of siRNA therapeutics |
title_full | Hydroxyethyl substituted linear polyethylenimine for safe and efficient delivery of siRNA therapeutics |
title_fullStr | Hydroxyethyl substituted linear polyethylenimine for safe and efficient delivery of siRNA therapeutics |
title_full_unstemmed | Hydroxyethyl substituted linear polyethylenimine for safe and efficient delivery of siRNA therapeutics |
title_short | Hydroxyethyl substituted linear polyethylenimine for safe and efficient delivery of siRNA therapeutics |
title_sort | hydroxyethyl substituted linear polyethylenimine for safe and efficient delivery of sirna therapeutics |
topic | Chemistry |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9087824/ https://www.ncbi.nlm.nih.gov/pubmed/35547911 http://dx.doi.org/10.1039/c8ra06298f |
work_keys_str_mv | AT patilsushilkumar hydroxyethylsubstitutedlinearpolyethylenimineforsafeandefficientdeliveryofsirnatherapeutics AT lalanirohan hydroxyethylsubstitutedlinearpolyethylenimineforsafeandefficientdeliveryofsirnatherapeutics AT bhattpriyanka hydroxyethylsubstitutedlinearpolyethylenimineforsafeandefficientdeliveryofsirnatherapeutics AT vhoraimran hydroxyethylsubstitutedlinearpolyethylenimineforsafeandefficientdeliveryofsirnatherapeutics AT patelvivek hydroxyethylsubstitutedlinearpolyethylenimineforsafeandefficientdeliveryofsirnatherapeutics AT patelhinal hydroxyethylsubstitutedlinearpolyethylenimineforsafeandefficientdeliveryofsirnatherapeutics AT misraambikanandan hydroxyethylsubstitutedlinearpolyethylenimineforsafeandefficientdeliveryofsirnatherapeutics |