Details
| Original language | English |
|---|---|
| Article number | 103135 |
| Journal | Journal of Drug Delivery Science and Technology |
| Volume | 69 |
| Early online date | 29 Jan 2022 |
| Publication status | Published - Mar 2022 |
Abstract
The effective delivery of nucleic acid therapeutics into tumor cells is of great importance in terms of cancer gene therapy. Successful application of siRNAs is restricted by the requirement to overcome several biological barriers, i.e. cell membrane penetration, endosomal escape, enzymatic degradation in cytosol, etc. Cationic polymers are promising delivery systems due to their biodegradability and effective binding with siRNA. A key characteristic of the particle trafficking into the cell is a noticeable change in pH during this process. This change can be used as a natural stimulus for pH-sensitive polymer particles. Such polymers are able to buffer the environment of a late endosome that leads to an abnormal flow of ions and water followed by endosomal swelling and disrupt and quick escape of the carriers into a cytoplasm. In present work, we synthesized a series of amphiphilic positively charged biocompatible pH-sensitive polypeptides forming polyplexes with nucleic acids. Four amino acids were used to compose the delivery systems, namely L-lysine, L-glutamic acid, L-phenylalanine and L-histidine. The number and the ratio of amino acids were varied in order to establish the optimal composition. The characteristics of polypeptides were studied by 1H NMR spectroscopy, high performance liquid chromatography and static light scattering. All synthesized polypeptides tended to a self-assembly in aqueous media and formed nanoparticles with hydrodynamic diameters ranging from 140 to 360 nm. The formation of polyplexes with short double-stranded oligonucleotides as a physicochemical siRNA model as well as the release of cargo in buffer media mimicking lysosome (pH∼5) and cytosol or bloodstream (pH 7.4) were studied. Cellular uptake of the particles was efficient and their cytotoxicity was negligible. Successful RNAi-mediated down-regulation of GFP gene expression was revealed in MDA-MB-231/GFP breast cancer cells. The amphiphilic polypeptides obtained can be considered as promising non-viral candidates for siRNA delivery.
Keywords
- Cancer treatment, Nanoparticles, pH-sensitive delivery systems, Polypeptide-based carriers, Self-assembly, siRNA delivery
ASJC Scopus subject areas
- Pharmacology, Toxicology and Pharmaceutics(all)
- Pharmaceutical Science
Sustainable Development Goals
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In: Journal of Drug Delivery Science and Technology, Vol. 69, 103135, 03.2022.
Research output: Contribution to journal › Article › Research › peer review
}
TY - JOUR
T1 - Amphiphilic pH-sensitive polypeptides for siRNA delivery
AU - Osipova, Olga
AU - Zakharova, Nataliia
AU - Pyankov, Ivan
AU - Egorova, Anna
AU - Kislova, Anastasia
AU - Lavrentieva, Antonina
AU - Kiselev, Anton
AU - Tennikova, Tatiana
AU - Korzhikova-Vlakh, Evgenia
N1 - Funding Information: The chemical and physico-chemical part of this work as well as the cytotoxicity and cellular uptake study were supported by Russian Foundation of Basic Research (RFBR , project #20-33-90181 ). The biological study on siRNA delivery into MDA-MB-231/GFP cells was carried out as a part of State Assignment from Ministry of Science and Higher Education of the Russian Federation ( #AAAA-A19-119,021,290,033-1 ). Funding Information: Ms. O. Osipova thanks G-RISC program for one-month scholarship (project #L-2020b-1) for a research work in the Institute of Technical Chemistry, Leibniz University of Hannover (Hannover, Germany). The authors are grateful to Prof. Arto Urtti and Dr. Marika Ruponen (University of Eastern Finland, Kuopio, Finland) for their help with the performance of gel electrophoresis assay. The authors express their gratitude to Magnetic Resonance, Chemical Analysis and Materials Research, Molecular and Cell Technologies and Optical and Laser Materials Research Centers of the Research Park of St. Petersburg State University. Funding Information: The chemical and physico-chemical part of this work as well as the cytotoxicity and cellular uptake study were supported by Russian Foundation of Basic Research (RFBR, project #20-33-90181). The biological study on siRNA delivery into MDA-MB-231/GFP cells was carried out as a part of State Assignment from Ministry of Science and Higher Education of the Russian Federation (#AAAA-A19-119,021,290,033-1).
PY - 2022/3
Y1 - 2022/3
N2 - The effective delivery of nucleic acid therapeutics into tumor cells is of great importance in terms of cancer gene therapy. Successful application of siRNAs is restricted by the requirement to overcome several biological barriers, i.e. cell membrane penetration, endosomal escape, enzymatic degradation in cytosol, etc. Cationic polymers are promising delivery systems due to their biodegradability and effective binding with siRNA. A key characteristic of the particle trafficking into the cell is a noticeable change in pH during this process. This change can be used as a natural stimulus for pH-sensitive polymer particles. Such polymers are able to buffer the environment of a late endosome that leads to an abnormal flow of ions and water followed by endosomal swelling and disrupt and quick escape of the carriers into a cytoplasm. In present work, we synthesized a series of amphiphilic positively charged biocompatible pH-sensitive polypeptides forming polyplexes with nucleic acids. Four amino acids were used to compose the delivery systems, namely L-lysine, L-glutamic acid, L-phenylalanine and L-histidine. The number and the ratio of amino acids were varied in order to establish the optimal composition. The characteristics of polypeptides were studied by 1H NMR spectroscopy, high performance liquid chromatography and static light scattering. All synthesized polypeptides tended to a self-assembly in aqueous media and formed nanoparticles with hydrodynamic diameters ranging from 140 to 360 nm. The formation of polyplexes with short double-stranded oligonucleotides as a physicochemical siRNA model as well as the release of cargo in buffer media mimicking lysosome (pH∼5) and cytosol or bloodstream (pH 7.4) were studied. Cellular uptake of the particles was efficient and their cytotoxicity was negligible. Successful RNAi-mediated down-regulation of GFP gene expression was revealed in MDA-MB-231/GFP breast cancer cells. The amphiphilic polypeptides obtained can be considered as promising non-viral candidates for siRNA delivery.
AB - The effective delivery of nucleic acid therapeutics into tumor cells is of great importance in terms of cancer gene therapy. Successful application of siRNAs is restricted by the requirement to overcome several biological barriers, i.e. cell membrane penetration, endosomal escape, enzymatic degradation in cytosol, etc. Cationic polymers are promising delivery systems due to their biodegradability and effective binding with siRNA. A key characteristic of the particle trafficking into the cell is a noticeable change in pH during this process. This change can be used as a natural stimulus for pH-sensitive polymer particles. Such polymers are able to buffer the environment of a late endosome that leads to an abnormal flow of ions and water followed by endosomal swelling and disrupt and quick escape of the carriers into a cytoplasm. In present work, we synthesized a series of amphiphilic positively charged biocompatible pH-sensitive polypeptides forming polyplexes with nucleic acids. Four amino acids were used to compose the delivery systems, namely L-lysine, L-glutamic acid, L-phenylalanine and L-histidine. The number and the ratio of amino acids were varied in order to establish the optimal composition. The characteristics of polypeptides were studied by 1H NMR spectroscopy, high performance liquid chromatography and static light scattering. All synthesized polypeptides tended to a self-assembly in aqueous media and formed nanoparticles with hydrodynamic diameters ranging from 140 to 360 nm. The formation of polyplexes with short double-stranded oligonucleotides as a physicochemical siRNA model as well as the release of cargo in buffer media mimicking lysosome (pH∼5) and cytosol or bloodstream (pH 7.4) were studied. Cellular uptake of the particles was efficient and their cytotoxicity was negligible. Successful RNAi-mediated down-regulation of GFP gene expression was revealed in MDA-MB-231/GFP breast cancer cells. The amphiphilic polypeptides obtained can be considered as promising non-viral candidates for siRNA delivery.
KW - Cancer treatment
KW - Nanoparticles
KW - pH-sensitive delivery systems
KW - Polypeptide-based carriers
KW - Self-assembly
KW - siRNA delivery
UR - http://www.scopus.com/inward/record.url?scp=85123826562&partnerID=8YFLogxK
U2 - 10.1016/j.jddst.2022.103135
DO - 10.1016/j.jddst.2022.103135
M3 - Article
AN - SCOPUS:85123826562
VL - 69
JO - Journal of Drug Delivery Science and Technology
JF - Journal of Drug Delivery Science and Technology
SN - 1773-2247
M1 - 103135
ER -