Design and Synthesis of Piperazine-Based Compounds Conjugated to Humanized Ferritin as Delivery System of siRNA in Cancer Cells
Gene expression regulation by small interfering RNA (siRNA) holds promise in treating a wide range of diseases through selective gene silencing. However, successful clinical application of nucleic acid-based therapy requires novel delivery options. Herein, to achieve efficient delivery of negatively...
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| Veröffentlicht in: | Bioconjugate chemistry 2021-06, Vol.32 (6), p.1105-1116 |
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| creator | Pediconi, Natalia Ghirga, Francesca Del Plato, Cristina Peruzzi, Giovanna Athanassopoulos, Constantinos M Mori, Mattia Crestoni, Maria Elisa Corinti, Davide Ugozzoli, Franco Massera, Chiara Arcovito, Alessandro Botta, Bruno Boffi, Alberto Quaglio, Deborah Baiocco, Paola |
| description | Gene expression regulation by small interfering RNA (siRNA) holds promise in treating a wide range of diseases through selective gene silencing. However, successful clinical application of nucleic acid-based therapy requires novel delivery options. Herein, to achieve efficient delivery of negatively charged siRNA duplexes, the internal cavity of “humanized” chimeric Archaeal ferritin (HumAfFt) was specifically decorated with novel cationic piperazine-based compounds (PAs). By coupling these rigid-rod-like amines with thiol-reactive reagents, chemoselective conjugation was efficiently afforded on topologically selected cysteine residues properly located inside HumAfFt. The capability of PAs-HumAfFt to host and deliver siRNA molecules through human transferrin receptor (TfR1), overexpressed in many cancer cells, was explored. These systems allowed siRNA delivery into HeLa, HepG2, and MCF-7 cancer cells with improved silencing effect on glyceraldehyde-3-phosphate dehydrogenase (GAPDH) gene expression with respect to traditional transfection methodologies and provided a promising TfR1-targeting system for multifunctional siRNA delivery to therapeutic applications. |
| doi_str_mv | 10.1021/acs.bioconjchem.1c00137 |
| format | Article |
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However, successful clinical application of nucleic acid-based therapy requires novel delivery options. Herein, to achieve efficient delivery of negatively charged siRNA duplexes, the internal cavity of “humanized” chimeric Archaeal ferritin (HumAfFt) was specifically decorated with novel cationic piperazine-based compounds (PAs). By coupling these rigid-rod-like amines with thiol-reactive reagents, chemoselective conjugation was efficiently afforded on topologically selected cysteine residues properly located inside HumAfFt. The capability of PAs-HumAfFt to host and deliver siRNA molecules through human transferrin receptor (TfR1), overexpressed in many cancer cells, was explored. These systems allowed siRNA delivery into HeLa, HepG2, and MCF-7 cancer cells with improved silencing effect on glyceraldehyde-3-phosphate dehydrogenase (GAPDH) gene expression with respect to traditional transfection methodologies and provided a promising TfR1-targeting system for multifunctional siRNA delivery to therapeutic applications.</description><identifier>ISSN: 1043-1802</identifier><identifier>EISSN: 1520-4812</identifier><identifier>DOI: 10.1021/acs.bioconjchem.1c00137</identifier><identifier>PMID: 33978420</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Amines ; Cancer ; Cell Line, Tumor ; Chemistry Techniques, Synthetic ; Conjugation ; Coupling (molecular) ; Drug Carriers - chemical synthesis ; Drug Carriers - chemistry ; Drug Design ; Ferritin ; Ferritins - chemistry ; Gene expression ; Gene regulation ; Gene silencing ; Glyceraldehyde-3-phosphate dehydrogenase ; Humans ; Nucleic acids ; Piperazine ; Piperazine - chemistry ; Reagents ; RNA, Small Interfering - chemistry ; RNA, Small Interfering - metabolism ; siRNA ; Therapeutic applications ; Transfection ; Transferrin ; Transferrins</subject><ispartof>Bioconjugate chemistry, 2021-06, Vol.32 (6), p.1105-1116</ispartof><rights>2021 The Authors. Published by American Chemical Society</rights><rights>Copyright American Chemical Society Jun 16, 2021</rights><rights>2021 The Authors. 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However, successful clinical application of nucleic acid-based therapy requires novel delivery options. Herein, to achieve efficient delivery of negatively charged siRNA duplexes, the internal cavity of “humanized” chimeric Archaeal ferritin (HumAfFt) was specifically decorated with novel cationic piperazine-based compounds (PAs). By coupling these rigid-rod-like amines with thiol-reactive reagents, chemoselective conjugation was efficiently afforded on topologically selected cysteine residues properly located inside HumAfFt. The capability of PAs-HumAfFt to host and deliver siRNA molecules through human transferrin receptor (TfR1), overexpressed in many cancer cells, was explored. These systems allowed siRNA delivery into HeLa, HepG2, and MCF-7 cancer cells with improved silencing effect on glyceraldehyde-3-phosphate dehydrogenase (GAPDH) gene expression with respect to traditional transfection methodologies and provided a promising TfR1-targeting system for multifunctional siRNA delivery to therapeutic applications.</description><subject>Amines</subject><subject>Cancer</subject><subject>Cell Line, Tumor</subject><subject>Chemistry Techniques, Synthetic</subject><subject>Conjugation</subject><subject>Coupling (molecular)</subject><subject>Drug Carriers - chemical synthesis</subject><subject>Drug Carriers - chemistry</subject><subject>Drug Design</subject><subject>Ferritin</subject><subject>Ferritins - chemistry</subject><subject>Gene expression</subject><subject>Gene regulation</subject><subject>Gene silencing</subject><subject>Glyceraldehyde-3-phosphate dehydrogenase</subject><subject>Humans</subject><subject>Nucleic acids</subject><subject>Piperazine</subject><subject>Piperazine - chemistry</subject><subject>Reagents</subject><subject>RNA, Small Interfering - chemistry</subject><subject>RNA, Small Interfering - metabolism</subject><subject>siRNA</subject><subject>Therapeutic applications</subject><subject>Transfection</subject><subject>Transferrin</subject><subject>Transferrins</subject><issn>1043-1802</issn><issn>1520-4812</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkU1v1DAQhi0EoqXwFyASFy5Z_BEnzgWppJQiVYD4OFuOM9n1KrG3dlJpe-lf76x2WRUunDz2vPOMX72EvGF0wShn741Ni9YFG_zarmBcMEspE9UTcsokp3mhGH-KNS1EzhTlJ-RFSmtKac0Uf05OhKgrVXB6Su4vILmlz4zvsp9bP63wmrLQZ9_dBqK5cx7yjyZBlzVh3ITZdwkrv56XZsLHKWRX82i8u8PLJcToJoewlF3A4G4hbhGaJhh3xOR-fD3PsN0YbyFmDQxDekme9WZI8OpwnpHfl59-NVf59bfPX5rz69wUqp5yxVlf8RpKJerCGmh7CZSVdWFoJVDRtVLWbVv3tKwshVK2gB6L1goqjLRcnJEPe-5mbkfoLPgpmkFvohtN3OpgnP67491KL8OtVlziAoGAdwdADDczpEmPLlm0YDyEOWkueclEWZQSpW__ka7DHD3aQ1WhJJVCMFRVe5WNIaUI_fEzjOpdyBpD1o9C1oeQcfL1Yy_HuT-pokDsBTvCcff_sA--Tbp9</recordid><startdate>20210616</startdate><enddate>20210616</enddate><creator>Pediconi, Natalia</creator><creator>Ghirga, Francesca</creator><creator>Del Plato, Cristina</creator><creator>Peruzzi, Giovanna</creator><creator>Athanassopoulos, Constantinos M</creator><creator>Mori, Mattia</creator><creator>Crestoni, Maria Elisa</creator><creator>Corinti, Davide</creator><creator>Ugozzoli, Franco</creator><creator>Massera, Chiara</creator><creator>Arcovito, Alessandro</creator><creator>Botta, Bruno</creator><creator>Boffi, Alberto</creator><creator>Quaglio, Deborah</creator><creator>Baiocco, Paola</creator><general>American Chemical Society</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QO</scope><scope>7TM</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0003-2398-1254</orcidid><orcidid>https://orcid.org/0000-0001-8707-4333</orcidid><orcidid>https://orcid.org/0000-0003-0230-1707</orcidid><orcidid>https://orcid.org/0000-0001-8064-3492</orcidid><orcidid>https://orcid.org/0000-0002-0991-5034</orcidid><orcidid>https://orcid.org/0000-0002-7549-1911</orcidid></search><sort><creationdate>20210616</creationdate><title>Design and Synthesis of Piperazine-Based Compounds Conjugated to Humanized Ferritin as Delivery System of siRNA in Cancer Cells</title><author>Pediconi, Natalia ; 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However, successful clinical application of nucleic acid-based therapy requires novel delivery options. Herein, to achieve efficient delivery of negatively charged siRNA duplexes, the internal cavity of “humanized” chimeric Archaeal ferritin (HumAfFt) was specifically decorated with novel cationic piperazine-based compounds (PAs). By coupling these rigid-rod-like amines with thiol-reactive reagents, chemoselective conjugation was efficiently afforded on topologically selected cysteine residues properly located inside HumAfFt. The capability of PAs-HumAfFt to host and deliver siRNA molecules through human transferrin receptor (TfR1), overexpressed in many cancer cells, was explored. These systems allowed siRNA delivery into HeLa, HepG2, and MCF-7 cancer cells with improved silencing effect on glyceraldehyde-3-phosphate dehydrogenase (GAPDH) gene expression with respect to traditional transfection methodologies and provided a promising TfR1-targeting system for multifunctional siRNA delivery to therapeutic applications.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>33978420</pmid><doi>10.1021/acs.bioconjchem.1c00137</doi><tpages>12</tpages><orcidid>https://orcid.org/0000-0003-2398-1254</orcidid><orcidid>https://orcid.org/0000-0001-8707-4333</orcidid><orcidid>https://orcid.org/0000-0003-0230-1707</orcidid><orcidid>https://orcid.org/0000-0001-8064-3492</orcidid><orcidid>https://orcid.org/0000-0002-0991-5034</orcidid><orcidid>https://orcid.org/0000-0002-7549-1911</orcidid><oa>free_for_read</oa></addata></record> |
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| ispartof | Bioconjugate chemistry, 2021-06, Vol.32 (6), p.1105-1116 |
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| source | ACS Publications; MEDLINE |
| subjects | Amines Cancer Cell Line, Tumor Chemistry Techniques, Synthetic Conjugation Coupling (molecular) Drug Carriers - chemical synthesis Drug Carriers - chemistry Drug Design Ferritin Ferritins - chemistry Gene expression Gene regulation Gene silencing Glyceraldehyde-3-phosphate dehydrogenase Humans Nucleic acids Piperazine Piperazine - chemistry Reagents RNA, Small Interfering - chemistry RNA, Small Interfering - metabolism siRNA Therapeutic applications Transfection Transferrin Transferrins |
| title | Design and Synthesis of Piperazine-Based Compounds Conjugated to Humanized Ferritin as Delivery System of siRNA in Cancer Cells |
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