Multifunctional Aptamer-miRNA Conjugates for Targeted Cancer Therapy
While microRNAs (miRNAs) clearly regulate multiple pathways integral to disease development and progression, the lack of safe and reliable means for specific delivery of miRNAs to target tissues represents a major obstacle to their broad therapeutic application. Our objective was to explore the use...
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| Veröffentlicht in: | Molecular therapy 2014-06, Vol.22 (6), p.1151-1163 |
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| creator | Esposito, Carla L Cerchia, Laura Catuogno, Silvia De Vita, Gennaro Dassie, Justin P Santamaria, Gianluca Swiderski, Piotr Condorelli, Gerolama Giangrande, Paloma H de Franciscis, Vittorio |
| description | While microRNAs (miRNAs) clearly regulate multiple pathways integral to disease development and progression, the lack of safe and reliable means for specific delivery of miRNAs to target tissues represents a major obstacle to their broad therapeutic application. Our objective was to explore the use of nucleic acid aptamers as carriers for cell-targeted delivery of a miRNA with tumor suppressor function, let-7g. Using an aptamer that binds to and antagonizes the oncogenic receptor tyrosine kinase Axl (GL21.T), here we describe the development of aptamer-miRNA conjugates as multifunctional molecules that inhibit the growth of Axl-expressing tumors. We conjugated the let-7g miRNA to GL21.T and demonstrate selective delivery to target cells, processing by the RNA interference machinery, and silencing of let-7g target genes. Importantly, the multifunctional conjugate reduced tumor growth in a xenograft model of lung adenocarcinoma. Therefore, our data establish aptamer-miRNA conjugates as a novel tool for targeted delivery of miRNAs with therapeutic potential. |
| doi_str_mv | 10.1038/mt.2014.5 |
| format | Article |
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Our objective was to explore the use of nucleic acid aptamers as carriers for cell-targeted delivery of a miRNA with tumor suppressor function, let-7g. Using an aptamer that binds to and antagonizes the oncogenic receptor tyrosine kinase Axl (GL21.T), here we describe the development of aptamer-miRNA conjugates as multifunctional molecules that inhibit the growth of Axl-expressing tumors. We conjugated the let-7g miRNA to GL21.T and demonstrate selective delivery to target cells, processing by the RNA interference machinery, and silencing of let-7g target genes. Importantly, the multifunctional conjugate reduced tumor growth in a xenograft model of lung adenocarcinoma. Therefore, our data establish aptamer-miRNA conjugates as a novel tool for targeted delivery of miRNAs with therapeutic potential.</description><identifier>ISSN: 1525-0016</identifier><identifier>EISSN: 1525-0024</identifier><identifier>DOI: 10.1038/mt.2014.5</identifier><identifier>PMID: 24441398</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Animals ; Aptamers, Nucleotide - metabolism ; Aptamers, Nucleotide - pharmacology ; Aptamers, Nucleotide - therapeutic use ; Cancer therapies ; Cell Line, Tumor ; Cell Survival ; Cells ; Female ; Gene Expression Regulation, Neoplastic ; Genes ; Humans ; Kinases ; Ligands ; Male ; MCF-7 Cells ; Mice, Nude ; MicroRNAs ; MicroRNAs - genetics ; MicroRNAs - pharmacology ; Molecular Targeted Therapy - methods ; Neoplasms - genetics ; Neoplasms - pathology ; Neoplasms - therapy ; Neoplasms, Experimental ; Organ Specificity ; Original ; Proto-Oncogene Proteins - antagonists & inhibitors ; Receptor Protein-Tyrosine Kinases - antagonists & inhibitors ; Targeted cancer therapy</subject><ispartof>Molecular therapy, 2014-06, Vol.22 (6), p.1151-1163</ispartof><rights>2014 The American Society of Gene & Cell Therapy</rights><rights>Copyright Nature Publishing Group Jun 2014</rights><rights>Copyright © 2014 The American Society of Gene & Cell Therapy 2014 The American Society of Gene & Cell Therapy</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c546t-bd40b54a46b5a8396f843fdb89e1ad7659887d62c782db632efa328ac096a3ab3</citedby><cites>FETCH-LOGICAL-c546t-bd40b54a46b5a8396f843fdb89e1ad7659887d62c782db632efa328ac096a3ab3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4048903/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4048903/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,723,776,780,881,27901,27902,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24441398$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Esposito, Carla L</creatorcontrib><creatorcontrib>Cerchia, Laura</creatorcontrib><creatorcontrib>Catuogno, Silvia</creatorcontrib><creatorcontrib>De Vita, Gennaro</creatorcontrib><creatorcontrib>Dassie, Justin P</creatorcontrib><creatorcontrib>Santamaria, Gianluca</creatorcontrib><creatorcontrib>Swiderski, Piotr</creatorcontrib><creatorcontrib>Condorelli, Gerolama</creatorcontrib><creatorcontrib>Giangrande, Paloma H</creatorcontrib><creatorcontrib>de Franciscis, Vittorio</creatorcontrib><title>Multifunctional Aptamer-miRNA Conjugates for Targeted Cancer Therapy</title><title>Molecular therapy</title><addtitle>Mol Ther</addtitle><description>While microRNAs (miRNAs) clearly regulate multiple pathways integral to disease development and progression, the lack of safe and reliable means for specific delivery of miRNAs to target tissues represents a major obstacle to their broad therapeutic application. Our objective was to explore the use of nucleic acid aptamers as carriers for cell-targeted delivery of a miRNA with tumor suppressor function, let-7g. Using an aptamer that binds to and antagonizes the oncogenic receptor tyrosine kinase Axl (GL21.T), here we describe the development of aptamer-miRNA conjugates as multifunctional molecules that inhibit the growth of Axl-expressing tumors. We conjugated the let-7g miRNA to GL21.T and demonstrate selective delivery to target cells, processing by the RNA interference machinery, and silencing of let-7g target genes. Importantly, the multifunctional conjugate reduced tumor growth in a xenograft model of lung adenocarcinoma. Therefore, our data establish aptamer-miRNA conjugates as a novel tool for targeted delivery of miRNAs with therapeutic potential.</description><subject>Animals</subject><subject>Aptamers, Nucleotide - metabolism</subject><subject>Aptamers, Nucleotide - pharmacology</subject><subject>Aptamers, Nucleotide - therapeutic use</subject><subject>Cancer therapies</subject><subject>Cell Line, Tumor</subject><subject>Cell Survival</subject><subject>Cells</subject><subject>Female</subject><subject>Gene Expression Regulation, Neoplastic</subject><subject>Genes</subject><subject>Humans</subject><subject>Kinases</subject><subject>Ligands</subject><subject>Male</subject><subject>MCF-7 Cells</subject><subject>Mice, Nude</subject><subject>MicroRNAs</subject><subject>MicroRNAs - genetics</subject><subject>MicroRNAs - pharmacology</subject><subject>Molecular Targeted Therapy - methods</subject><subject>Neoplasms - genetics</subject><subject>Neoplasms - pathology</subject><subject>Neoplasms - therapy</subject><subject>Neoplasms, Experimental</subject><subject>Organ Specificity</subject><subject>Original</subject><subject>Proto-Oncogene Proteins - 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metabolism</topic><topic>Aptamers, Nucleotide - pharmacology</topic><topic>Aptamers, Nucleotide - therapeutic use</topic><topic>Cancer therapies</topic><topic>Cell Line, Tumor</topic><topic>Cell Survival</topic><topic>Cells</topic><topic>Female</topic><topic>Gene Expression Regulation, Neoplastic</topic><topic>Genes</topic><topic>Humans</topic><topic>Kinases</topic><topic>Ligands</topic><topic>Male</topic><topic>MCF-7 Cells</topic><topic>Mice, Nude</topic><topic>MicroRNAs</topic><topic>MicroRNAs - genetics</topic><topic>MicroRNAs - pharmacology</topic><topic>Molecular Targeted Therapy - methods</topic><topic>Neoplasms - genetics</topic><topic>Neoplasms - pathology</topic><topic>Neoplasms - therapy</topic><topic>Neoplasms, Experimental</topic><topic>Organ Specificity</topic><topic>Original</topic><topic>Proto-Oncogene Proteins - antagonists & inhibitors</topic><topic>Receptor Protein-Tyrosine Kinases - antagonists & inhibitors</topic><topic>Targeted cancer therapy</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Esposito, Carla L</creatorcontrib><creatorcontrib>Cerchia, Laura</creatorcontrib><creatorcontrib>Catuogno, Silvia</creatorcontrib><creatorcontrib>De Vita, Gennaro</creatorcontrib><creatorcontrib>Dassie, Justin P</creatorcontrib><creatorcontrib>Santamaria, Gianluca</creatorcontrib><creatorcontrib>Swiderski, Piotr</creatorcontrib><creatorcontrib>Condorelli, Gerolama</creatorcontrib><creatorcontrib>Giangrande, Paloma H</creatorcontrib><creatorcontrib>de Franciscis, Vittorio</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Biological Science Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>MEDLINE - Academic</collection><collection>Biotechnology Research Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Molecular therapy</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Esposito, Carla L</au><au>Cerchia, Laura</au><au>Catuogno, Silvia</au><au>De Vita, Gennaro</au><au>Dassie, Justin P</au><au>Santamaria, Gianluca</au><au>Swiderski, Piotr</au><au>Condorelli, Gerolama</au><au>Giangrande, Paloma H</au><au>de Franciscis, Vittorio</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Multifunctional Aptamer-miRNA Conjugates for Targeted Cancer Therapy</atitle><jtitle>Molecular therapy</jtitle><addtitle>Mol Ther</addtitle><date>2014-06-01</date><risdate>2014</risdate><volume>22</volume><issue>6</issue><spage>1151</spage><epage>1163</epage><pages>1151-1163</pages><issn>1525-0016</issn><eissn>1525-0024</eissn><abstract>While microRNAs (miRNAs) clearly regulate multiple pathways integral to disease development and progression, the lack of safe and reliable means for specific delivery of miRNAs to target tissues represents a major obstacle to their broad therapeutic application. Our objective was to explore the use of nucleic acid aptamers as carriers for cell-targeted delivery of a miRNA with tumor suppressor function, let-7g. Using an aptamer that binds to and antagonizes the oncogenic receptor tyrosine kinase Axl (GL21.T), here we describe the development of aptamer-miRNA conjugates as multifunctional molecules that inhibit the growth of Axl-expressing tumors. We conjugated the let-7g miRNA to GL21.T and demonstrate selective delivery to target cells, processing by the RNA interference machinery, and silencing of let-7g target genes. Importantly, the multifunctional conjugate reduced tumor growth in a xenograft model of lung adenocarcinoma. Therefore, our data establish aptamer-miRNA conjugates as a novel tool for targeted delivery of miRNAs with therapeutic potential.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>24441398</pmid><doi>10.1038/mt.2014.5</doi><tpages>13</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Animals Aptamers, Nucleotide - metabolism Aptamers, Nucleotide - pharmacology Aptamers, Nucleotide - therapeutic use Cancer therapies Cell Line, Tumor Cell Survival Cells Female Gene Expression Regulation, Neoplastic Genes Humans Kinases Ligands Male MCF-7 Cells Mice, Nude MicroRNAs MicroRNAs - genetics MicroRNAs - pharmacology Molecular Targeted Therapy - methods Neoplasms - genetics Neoplasms - pathology Neoplasms - therapy Neoplasms, Experimental Organ Specificity Original Proto-Oncogene Proteins - antagonists & inhibitors Receptor Protein-Tyrosine Kinases - antagonists & inhibitors Targeted cancer therapy |
| title | Multifunctional Aptamer-miRNA Conjugates for Targeted Cancer Therapy |
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