Cyclodextrin-Based Nanostructure Efficiently Delivers siRNA to Glioblastoma Cells Preferentially via Macropinocytosis
Small interfering ribonucleic acid (siRNA) has the potential to revolutionize therapeutics since it can knockdown very efficiently the target protein. It is starting to be widely used to interfere with cell infection by HIV. However, naked siRNAs are unable to get into the cell, requiring the use of...
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| Veröffentlicht in: | International journal of molecular sciences 2020-12, Vol.21 (23), p.9306 |
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| creator | Manzanares, Darío Pérez-Carrión, María Dolores Jiménez Blanco, José Luis Ortiz Mellet, Carmen García Fernández, José Manuel Ceña, Valentín |
| description | Small interfering ribonucleic acid (siRNA) has the potential to revolutionize therapeutics since it can knockdown very efficiently the target protein. It is starting to be widely used to interfere with cell infection by HIV. However, naked siRNAs are unable to get into the cell, requiring the use of carriers to protect them from degradation and transporting them across the cell membrane. There is no information about which is the most efficient endocytosis route for high siRNA transfection efficiency. One of the most promising carriers to efficiently deliver siRNA are cyclodextrin derivatives. We have used nanocomplexes composed of siRNA and a β-cyclodextrin derivative, AMC6, with a very high transfection efficiency to selectively knockdown clathrin heavy chain, caveolin 1, and p21 Activated Kinase 1 to specifically block clathrin-mediated, caveolin-mediated and macropinocytosis endocytic pathways. The main objective was to identify whether there is a preferential endocytic pathway associated with high siRNA transfection efficiency. We have found that macropinocytosis is the preferential entry pathway for the nanoparticle and its associated siRNA cargo. However, blockade of macropinocytosis does not affect AMC6-mediated transfection efficiency, suggesting that macropinocytosis blockade can be functionally compensated by an increase in clathrin- and caveolin-mediated endocytosis. |
| doi_str_mv | 10.3390/ijms21239306 |
| format | Article |
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It is starting to be widely used to interfere with cell infection by HIV. However, naked siRNAs are unable to get into the cell, requiring the use of carriers to protect them from degradation and transporting them across the cell membrane. There is no information about which is the most efficient endocytosis route for high siRNA transfection efficiency. One of the most promising carriers to efficiently deliver siRNA are cyclodextrin derivatives. We have used nanocomplexes composed of siRNA and a β-cyclodextrin derivative, AMC6, with a very high transfection efficiency to selectively knockdown clathrin heavy chain, caveolin 1, and p21 Activated Kinase 1 to specifically block clathrin-mediated, caveolin-mediated and macropinocytosis endocytic pathways. The main objective was to identify whether there is a preferential endocytic pathway associated with high siRNA transfection efficiency. We have found that macropinocytosis is the preferential entry pathway for the nanoparticle and its associated siRNA cargo. However, blockade of macropinocytosis does not affect AMC6-mediated transfection efficiency, suggesting that macropinocytosis blockade can be functionally compensated by an increase in clathrin- and caveolin-mediated endocytosis.</description><identifier>ISSN: 1422-0067</identifier><identifier>ISSN: 1661-6596</identifier><identifier>EISSN: 1422-0067</identifier><identifier>DOI: 10.3390/ijms21239306</identifier><identifier>PMID: 33291321</identifier><language>eng</language><publisher>Switzerland: MDPI AG</publisher><subject>Animals ; beta-Cyclodextrins - chemistry ; Brain cancer ; Brain Neoplasms - metabolism ; Caveolin ; Caveolin-1 ; Cell Line, Tumor ; Cell membranes ; Clathrin ; Cyclodextrins ; Efficiency ; Endocytosis ; Glioblastoma ; Glioblastoma - metabolism ; Glioblastoma cells ; Humans ; Kinases ; Nanoparticles ; Nanoparticles - chemistry ; Nanoparticles - metabolism ; p21-activated kinase ; Pinocytosis ; Proteins ; Rats ; RNA, Small Interfering - genetics ; siRNA ; Transfection ; Transfection - methods ; β-Cyclodextrin</subject><ispartof>International journal of molecular sciences, 2020-12, Vol.21 (23), p.9306</ispartof><rights>2020. This work is licensed under http://creativecommons.org/licenses/by/3.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2020 by the authors. 2020</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c412t-fbff551e6396631396686cc1f9ce41f6efe077198d8798ffd826bd64e7a9e5383</citedby><cites>FETCH-LOGICAL-c412t-fbff551e6396631396686cc1f9ce41f6efe077198d8798ffd826bd64e7a9e5383</cites><orcidid>0000-0003-3035-6449 ; 0000-0002-7676-7721 ; 0000-0002-5249-9013 ; 0000-0002-6827-0387 ; 0000-0001-8928-3681</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7731237/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7731237/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,881,27903,27904,53769,53771</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/33291321$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Manzanares, Darío</creatorcontrib><creatorcontrib>Pérez-Carrión, María Dolores</creatorcontrib><creatorcontrib>Jiménez Blanco, José Luis</creatorcontrib><creatorcontrib>Ortiz Mellet, Carmen</creatorcontrib><creatorcontrib>García Fernández, José Manuel</creatorcontrib><creatorcontrib>Ceña, Valentín</creatorcontrib><title>Cyclodextrin-Based Nanostructure Efficiently Delivers siRNA to Glioblastoma Cells Preferentially via Macropinocytosis</title><title>International journal of molecular sciences</title><addtitle>Int J Mol Sci</addtitle><description>Small interfering ribonucleic acid (siRNA) has the potential to revolutionize therapeutics since it can knockdown very efficiently the target protein. 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It is starting to be widely used to interfere with cell infection by HIV. However, naked siRNAs are unable to get into the cell, requiring the use of carriers to protect them from degradation and transporting them across the cell membrane. There is no information about which is the most efficient endocytosis route for high siRNA transfection efficiency. One of the most promising carriers to efficiently deliver siRNA are cyclodextrin derivatives. We have used nanocomplexes composed of siRNA and a β-cyclodextrin derivative, AMC6, with a very high transfection efficiency to selectively knockdown clathrin heavy chain, caveolin 1, and p21 Activated Kinase 1 to specifically block clathrin-mediated, caveolin-mediated and macropinocytosis endocytic pathways. The main objective was to identify whether there is a preferential endocytic pathway associated with high siRNA transfection efficiency. We have found that macropinocytosis is the preferential entry pathway for the nanoparticle and its associated siRNA cargo. However, blockade of macropinocytosis does not affect AMC6-mediated transfection efficiency, suggesting that macropinocytosis blockade can be functionally compensated by an increase in clathrin- and caveolin-mediated endocytosis.</abstract><cop>Switzerland</cop><pub>MDPI AG</pub><pmid>33291321</pmid><doi>10.3390/ijms21239306</doi><orcidid>https://orcid.org/0000-0003-3035-6449</orcidid><orcidid>https://orcid.org/0000-0002-7676-7721</orcidid><orcidid>https://orcid.org/0000-0002-5249-9013</orcidid><orcidid>https://orcid.org/0000-0002-6827-0387</orcidid><orcidid>https://orcid.org/0000-0001-8928-3681</orcidid><oa>free_for_read</oa></addata></record> |
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| source | MDPI - Multidisciplinary Digital Publishing Institute; MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central |
| subjects | Animals beta-Cyclodextrins - chemistry Brain cancer Brain Neoplasms - metabolism Caveolin Caveolin-1 Cell Line, Tumor Cell membranes Clathrin Cyclodextrins Efficiency Endocytosis Glioblastoma Glioblastoma - metabolism Glioblastoma cells Humans Kinases Nanoparticles Nanoparticles - chemistry Nanoparticles - metabolism p21-activated kinase Pinocytosis Proteins Rats RNA, Small Interfering - genetics siRNA Transfection Transfection - methods β-Cyclodextrin |
| title | Cyclodextrin-Based Nanostructure Efficiently Delivers siRNA to Glioblastoma Cells Preferentially via Macropinocytosis |
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