Cyclam-Modified Polyethyleneimine for Simultaneous TGFβ siRNA Delivery and CXCR4 Inhibition for the Treatment of CCl4-Induced Liver Fibrosis
© 2021 Ullah et al..
BACKGROUND: Liver fibrosis is a chronic liver disease with excessive production of extracellular matrix proteins, leading to cirrhosis, hepatocellular carcinoma, and death.
PURPOSE: This study aimed at the development of a novel derivative of polyethyleneimine (PEI) that can effectively deliver transforming growth factor β (TGFβ) siRNA and inhibit chemokine receptor 4 (CXCR4) for TGFβ silencing and CXCR4 Inhibition, respectively, to treat CCl4-induced liver fibrosis in a mouse model.
METHODS: Cyclam-modified PEI (PEI-Cyclam) was synthesized by incorporating cyclam moiety into PEI by nucleophilic substitution reaction. Gel electrophoresis confirmed the PEI-Cyclam polyplex formation and stability against RNAase and serum degradation. Transmission electron microscopy and zeta sizer were employed for the morphology, particle size, and zeta potential, respectively. The gene silencing and CXCR4 targeting abilities of PEI-Cyclam polyplex were evaluated by luciferase and CXCR4 redistribution assays, respectively. The histological and immunohistochemical staining determined the anti-fibrotic activity of PEI-Cyclam polyplex. The TGFβ silencing of PEI-Cyclam polyplex was authenticated by Western blotting.
RESULTS: The 1H NMR of PEI-Cyclam exhibited successful incorporation of cyclam content onto PEI. The PEI-Cyclam polyplex displayed spherical morphology, positive surface charge, and stability against RNAse and serum degradation. Cyclam modification decreased the cytotoxicity and demonstrated CXCR4 antagonistic and luciferase gene silencing efficiency. PEI-Cyclam/siTGFβ polyplexes decreased inflammation, collagen deposition, apoptosis, and cell proliferation, thus ameliorating liver fibrosis. Also, PEI-Cyclam/siTGFβ polyplex significantly downregulated α-smooth muscle actin, TGFβ, and collagen type III.
CONCLUSION: Our findings validate the feasibility of using PEI-Cyclam as a siRNA delivery vector for simultaneous TGFβ siRNA delivery and CXCR4 inhibition for the combined anti-fibrotic effects in a setting of CCl4-induced liver fibrosis.
| Errataetall: |
ErratumIn: Int J Nanomedicine. 2021 Sep 07;16:6203-6204. - PMID 34522096 |
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| Medienart: |
E-Artikel |
| Erscheinungsjahr: |
2021 |
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| Erschienen: |
2021 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:16 |
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| Enthalten in: |
International journal of nanomedicine - 16(2021) vom: 07., Seite 4451-4470 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Ullah, Aftab [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 14.07.2021 Date Revised 24.04.2022 published: Electronic-eCollection ErratumIn: Int J Nanomedicine. 2021 Sep 07;16:6203-6204. - PMID 34522096 Citation Status MEDLINE |
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| doi: |
10.2147/IJN.S314367 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM327804238 |
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| 245 | 1 | 0 | |a Cyclam-Modified Polyethyleneimine for Simultaneous TGFβ siRNA Delivery and CXCR4 Inhibition for the Treatment of CCl4-Induced Liver Fibrosis |
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| 500 | |a Date Completed 14.07.2021 | ||
| 500 | |a Date Revised 24.04.2022 | ||
| 500 | |a published: Electronic-eCollection | ||
| 500 | |a ErratumIn: Int J Nanomedicine. 2021 Sep 07;16:6203-6204. - PMID 34522096 | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2021 Ullah et al. | ||
| 520 | |a BACKGROUND: Liver fibrosis is a chronic liver disease with excessive production of extracellular matrix proteins, leading to cirrhosis, hepatocellular carcinoma, and death | ||
| 520 | |a PURPOSE: This study aimed at the development of a novel derivative of polyethyleneimine (PEI) that can effectively deliver transforming growth factor β (TGFβ) siRNA and inhibit chemokine receptor 4 (CXCR4) for TGFβ silencing and CXCR4 Inhibition, respectively, to treat CCl4-induced liver fibrosis in a mouse model | ||
| 520 | |a METHODS: Cyclam-modified PEI (PEI-Cyclam) was synthesized by incorporating cyclam moiety into PEI by nucleophilic substitution reaction. Gel electrophoresis confirmed the PEI-Cyclam polyplex formation and stability against RNAase and serum degradation. Transmission electron microscopy and zeta sizer were employed for the morphology, particle size, and zeta potential, respectively. The gene silencing and CXCR4 targeting abilities of PEI-Cyclam polyplex were evaluated by luciferase and CXCR4 redistribution assays, respectively. The histological and immunohistochemical staining determined the anti-fibrotic activity of PEI-Cyclam polyplex. The TGFβ silencing of PEI-Cyclam polyplex was authenticated by Western blotting | ||
| 520 | |a RESULTS: The 1H NMR of PEI-Cyclam exhibited successful incorporation of cyclam content onto PEI. The PEI-Cyclam polyplex displayed spherical morphology, positive surface charge, and stability against RNAse and serum degradation. Cyclam modification decreased the cytotoxicity and demonstrated CXCR4 antagonistic and luciferase gene silencing efficiency. PEI-Cyclam/siTGFβ polyplexes decreased inflammation, collagen deposition, apoptosis, and cell proliferation, thus ameliorating liver fibrosis. Also, PEI-Cyclam/siTGFβ polyplex significantly downregulated α-smooth muscle actin, TGFβ, and collagen type III | ||
| 520 | |a CONCLUSION: Our findings validate the feasibility of using PEI-Cyclam as a siRNA delivery vector for simultaneous TGFβ siRNA delivery and CXCR4 inhibition for the combined anti-fibrotic effects in a setting of CCl4-induced liver fibrosis | ||
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