The proton sponge: a trick to enter cells the viruses did not exploit
Open accessAbstract
Several non-permanent polycations possessing substantial buffering capacity below physiological pH, such as lipopolyamines and polyethylenimines, are efficient transfection agents per se, i.e. without the addition of lysosomotropic bases, or cell targeting, or membrane disruption agents. These vectors have been shown to deliver genes as well as oligonucleotides both in vitro and in vivo. Our hypothesis is that their efficiency relies on extensive endosome swelling and rupture that provides an escape mechanism for the polycation/DNA particles.
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2° and 3° amines on polymer chains can be protonated inside endo-lysosomes and counterbalance chloride ions flow, creating osmotic gradient leading to swelling and bursting and releasing polyplex into cytosol.
“Briefly, 2° and 3° amines on polymer chains can be protonated inside endo-lysosomes and then counterbalance chloride ions flow into the vesicles. This process creates an osmotic gradient between the exterior and interior of the endo-lysosomes, leading to swelling and bursting of these vesicles and releasing the polyplex into the cytosol [178].”
From Non-viral delivery systems for CRISPR/Cas9-based genome editing: challenges and opportunities (2018) · cites this paper as [178]
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Behr, M. P., Zhou, J., Xu, B., & Zhang, H. (2021) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2021.05.020 · Cited by 225 · see citing works
Ahmadzada, T., Reid, G., & McKenzie, D. R. (2018) · Biophysical Reviews · doi:10.1007/s12551-017-0392-1 · Cited by 224 · see citing works
“A commonly used approach is to make use of the proton sponge effect (Behr 1997), which is based on the hypothesis that pH buffering can facilitate escape from the endocytic pathway by preventing the acidification of the endosomes (Arnold et al. 2017; Dong et al. 2015; Gujrati et al. 2016; Li et al.…”
MethodExploiting Endocytosis for NanomedicinesPreprint
Akinc, A., & Battaglia, G. (2013) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a016980 · Cited by 215 · see citing works
Polycation cytotoxicity: a delicate matter for nucleic acid therapy—focus on polyethylenimine
Parhamifar, L., Larsen, A. K., Hunter, A. C., et al. (2010) · Soft Matter · doi:10.1039/c000190b · Cited by 213 · see citing works
Polymeric delivery systems for nucleic acid therapeutics: Approaching the clinic
van den Berg, A. I. S., Yun, C., Schiffelers, R. M., & Hennink, W. E. (2021) · Journal of Controlled Release · doi:10.1016/j.jconrel.2021.01.014 · Cited by 215 · see citing works
Gene Transfer by Means of Lipo- and Polyplexes: Role of Clathrin and Caveolae-Mediated Endocytosis
Rejman, J., Conese, M., & Hoekstra, D. (2006) · Journal of Liposome Research · doi:10.1080/08982100600848819 · Cited by 207 · see citing works
Liu, X., Zhou, J., Yu, T., Chen, C., Cheng, Q., Sengupta, K., Huang, Y., Li, H., Liu, C., Wang, Y., et al. (2014) · Angewandte Chemie International Edition · doi:10.1002/anie.201406764 · Cited by 206 · see citing works
RetractedAigner, A. M. (2006) · Journal of Biotechnology · doi:10.1016/j.jbiotec.2005.12.003 · Cited by 202 · see citing works
Efficient gene delivery by urocanic acid-modified chitosan
Kim, T. H., Ihm, J. E., Choi, Y. J., Nah, J. W., & Cho, C. S. (2003) · Journal of Controlled Release · doi:10.1016/j.jconrel.2003.08.017 · Cited by 203 · see citing works
Polyethylenimines for siRNA and miRNA delivery in vivo
Höbel, S., & Aigner, A. M. (2013) · Wiley Interdisciplinary Reviews Nanomedicine and Nanobiotechnology · doi:10.1002/wnan.1228 · Cited by 210 · see citing works
Itaka, K., Harada, A., Yamasaki, Y., Nakamura, K., Kawaguchi, H., & Kataoka, K. (2004) · The Journal of Gene Medicine · doi:10.1002/jgm.470 · Cited by 201 · see citing works
“Thus, PEI in the endosome interferes with pH lowering of the compartment, and induces an increased ion osmotic pressure to cause endosomal swelling and subsequent disruption [6].”
BackgroundWahane, A. V., Waghmode, A., Kapphahn, A., Dhuri, K., Gupta, A., & Bahal, R. (2020) · Molecules · doi:10.3390/molecules25122866 · Cited by 202 · see citing works
“The higher transfection efficiency of PEI is attributed to the buffering capacity of multiple amino groups on PEI, which can quench protons pumped by the vesicular ATPase proton pump present on the endosomes [77].”
BackgroundLiposome–polyethylenimine complexes for enhanced DNA and siRNA delivery
Schäfer, J., Höbel, S., Bakowsky, U., & Aigner, A. M. (2010) · Biomaterials · doi:10.1016/j.biomaterials.2010.05.043 · Cited by 196 · see citing works
Ngamcherdtrakul, W., Morry, J., Gu, S., Castro, D. J., Goodyear, S. M., Sangvanich, T., Reda, M. M., Lee, R., Mihelic, S. A., Beckman, B. L., et al. (2015) · Advanced Functional Materials · doi:10.1002/adfm.201404629 · Cited by 198 · see citing works
Malek, A. V., Merkel, O. M., Fink, L., Czubayko, F., Kissel, T., & Aigner, A. M. (2009) · Toxicology and Applied Pharmacology · doi:10.1016/j.taap.2009.01.014 · Cited by 185 · see citing works
Gene delivery by cationic lipids: in and out of an endosome
Hoekstra, D., Rejman, J., Wasungu, L., Shi, F., & Zuhorn, I. S. (2007) · Biochemical Society Transactions · doi:10.1042/bst0350068 · Cited by 186 · see citing works
- Authors
- Behr, J.-P.
- Affiliations
- Centre National de la Recherche Scientifique (FR)
- Corresponding author
- Behr, Jean-Paul
- Venue
- CHIMIA
- Publisher
- Swiss Chemical Society
- Published
- 1997-02-26
- Volume
- 51
- Issue
- 1-2
- Pages
- 34
- ISSN
- 0009-4293 (ISSN-L)
- 2673-2424
- OpenAlex
- W4292328694
- Cited by
- 933
- References
- 1
- Citations by year
- 2026: 18 · 2025: 31 · 2024: 30 · 2023: 34 · 2022: 24 · 2021: 41 · 2020: 56 · 2019: 47 · 2018: 50 · 2017: 38 · 2016: 58 · 2015: 50 · 2014: 55 · 2013: 78 · 2012: 49
- FWCI
- 1.07
- Type
- journal article
- Language
- en
- Open access
- diamond
- doi.org
- Licence
- Locations
- CHIMIA International Journal for Chemistry (publishedVersion, cc-by-nc)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
- Physical Sciences › Materials Science › Polymers and Plastics › Dendrimers and Hyperbranched Polymers
- Keywords
- proton sponge, polyethyleneimine, endosomal escape, gene delivery, oligonucleotide delivery, buffering capacity
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