Receptor-targeted liposome-peptide nanocomplexes for siRNA delivery
Abstract RNA interference induced by double-stranded, small interfering RNA (siRNA) molecules has attracted great attention as a genetic therapeutic approach. Despite major advances in this field, new nanoparticle formulations are required for in vivo delivery of siRNA, particularly for tissue-speci...
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| Veröffentlicht in: | Biomaterials 2011-09, Vol.32 (26), p.6302-6315 |
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| creator | Tagalakis, Aristides D He, Lin Saraiva, Luisa Gustafsson, Kenth T Hart, Stephen L |
| description | Abstract RNA interference induced by double-stranded, small interfering RNA (siRNA) molecules has attracted great attention as a genetic therapeutic approach. Despite major advances in this field, new nanoparticle formulations are required for in vivo delivery of siRNA, particularly for tissue-specific delivery of siRNA reagents. We have developed and optimized LYR nanocomplex formulations for siRNA delivery that consist of a liposome (DOTMA/DOPE; L) and a targeting peptide (K16 GACYGLPHKFCG; Y) which self-assemble on mixing at optimal ratios with siRNA (R). Biophysical measurements indicated that LYR nanocomplexes were strongly cationic, mainly spherical particles of less than 100 nm. These formulations packaged and protected siRNA on incubation with RNAseA with >90% intact siRNA recovery. In addition, intact siRNA was recovered from LYRs upon heparin treatment. A critical synergy was observed between the lipid and peptide components for LYR particle stability and transfection efficiency. To evaluate targeting, transfections were compared with non-targeted formulations containing K16 with no targeting ligand. Gene knockdown efficiencies with targeted formulations were more than two-fold better in all cell lines tested ( p |
| doi_str_mv | 10.1016/j.biomaterials.2011.05.022 |
| format | Article |
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Despite major advances in this field, new nanoparticle formulations are required for in vivo delivery of siRNA, particularly for tissue-specific delivery of siRNA reagents. We have developed and optimized LYR nanocomplex formulations for siRNA delivery that consist of a liposome (DOTMA/DOPE; L) and a targeting peptide (K16 GACYGLPHKFCG; Y) which self-assemble on mixing at optimal ratios with siRNA (R). Biophysical measurements indicated that LYR nanocomplexes were strongly cationic, mainly spherical particles of less than 100 nm. These formulations packaged and protected siRNA on incubation with RNAseA with >90% intact siRNA recovery. In addition, intact siRNA was recovered from LYRs upon heparin treatment. A critical synergy was observed between the lipid and peptide components for LYR particle stability and transfection efficiency. To evaluate targeting, transfections were compared with non-targeted formulations containing K16 with no targeting ligand. Gene knockdown efficiencies with targeted formulations were more than two-fold better in all cell lines tested ( p < 0.01). LYR formulations with liposomes containing DOTMA, which has an 18-carbon (C18) alkyl tail, were significantly better in silencing than formulations containing cationic lipids with shorter alkyl tails. LYRs with siRNA against endogenous luciferase and GAPDH were successful in silencing these genes in 3 cell lines (1HAEo- human airway epithelial, B104 rat neuroblastoma, Neuro2A-Luc mouse neuroblastoma) in vitro with 80% efficiency, similar in efficiency to Lipofectamine 2000. Confocal microscopy analysis with LYRs containing fluorescently labelled siRNA (Cy3) showed that the siRNA was located in the perinuclear region of the cytoplasm, where the RNA-induced silencing complex (RISC) is likely to be found. The LYR formulations may have applications for the further development of siRNA-based therapeutics.</description><identifier>ISSN: 0142-9612</identifier><identifier>EISSN: 1878-5905</identifier><identifier>DOI: 10.1016/j.biomaterials.2011.05.022</identifier><identifier>PMID: 21624650</identifier><language>eng</language><publisher>Netherlands: Elsevier Ltd</publisher><subject>Advanced Basic Science ; Animals ; Cell Line ; Cell Line, Tumor ; Cell Proliferation ; Dentistry ; Gene silencing ; Gene Silencing - physiology ; Heparin - chemistry ; Humans ; Liposomes ; Liposomes - chemistry ; Microscopy, Confocal ; Microscopy, Electron ; Microscopy, Electron, Transmission ; Nanoconjugates - chemistry ; Nanoparticle ; Peptides - chemistry ; Rats ; RNA Interference ; RNA, Small Interfering - administration & dosage ; RNA, Small Interfering - chemistry ; siRNA delivery ; Targeting</subject><ispartof>Biomaterials, 2011-09, Vol.32 (26), p.6302-6315</ispartof><rights>Elsevier Ltd</rights><rights>2011 Elsevier Ltd</rights><rights>Copyright © 2011 Elsevier Ltd. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c532t-cab2a50ffd3599cc4b2c5c849c2d8a4df64d79d58a23b3ea2a483196ef07a3a43</citedby><cites>FETCH-LOGICAL-c532t-cab2a50ffd3599cc4b2c5c849c2d8a4df64d79d58a23b3ea2a483196ef07a3a43</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0142961211005412$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/21624650$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Tagalakis, Aristides D</creatorcontrib><creatorcontrib>He, Lin</creatorcontrib><creatorcontrib>Saraiva, Luisa</creatorcontrib><creatorcontrib>Gustafsson, Kenth T</creatorcontrib><creatorcontrib>Hart, Stephen L</creatorcontrib><title>Receptor-targeted liposome-peptide nanocomplexes for siRNA delivery</title><title>Biomaterials</title><addtitle>Biomaterials</addtitle><description>Abstract RNA interference induced by double-stranded, small interfering RNA (siRNA) molecules has attracted great attention as a genetic therapeutic approach. Despite major advances in this field, new nanoparticle formulations are required for in vivo delivery of siRNA, particularly for tissue-specific delivery of siRNA reagents. We have developed and optimized LYR nanocomplex formulations for siRNA delivery that consist of a liposome (DOTMA/DOPE; L) and a targeting peptide (K16 GACYGLPHKFCG; Y) which self-assemble on mixing at optimal ratios with siRNA (R). Biophysical measurements indicated that LYR nanocomplexes were strongly cationic, mainly spherical particles of less than 100 nm. These formulations packaged and protected siRNA on incubation with RNAseA with >90% intact siRNA recovery. In addition, intact siRNA was recovered from LYRs upon heparin treatment. A critical synergy was observed between the lipid and peptide components for LYR particle stability and transfection efficiency. To evaluate targeting, transfections were compared with non-targeted formulations containing K16 with no targeting ligand. Gene knockdown efficiencies with targeted formulations were more than two-fold better in all cell lines tested ( p < 0.01). LYR formulations with liposomes containing DOTMA, which has an 18-carbon (C18) alkyl tail, were significantly better in silencing than formulations containing cationic lipids with shorter alkyl tails. LYRs with siRNA against endogenous luciferase and GAPDH were successful in silencing these genes in 3 cell lines (1HAEo- human airway epithelial, B104 rat neuroblastoma, Neuro2A-Luc mouse neuroblastoma) in vitro with 80% efficiency, similar in efficiency to Lipofectamine 2000. Confocal microscopy analysis with LYRs containing fluorescently labelled siRNA (Cy3) showed that the siRNA was located in the perinuclear region of the cytoplasm, where the RNA-induced silencing complex (RISC) is likely to be found. The LYR formulations may have applications for the further development of siRNA-based therapeutics.</description><subject>Advanced Basic Science</subject><subject>Animals</subject><subject>Cell Line</subject><subject>Cell Line, Tumor</subject><subject>Cell Proliferation</subject><subject>Dentistry</subject><subject>Gene silencing</subject><subject>Gene Silencing - physiology</subject><subject>Heparin - chemistry</subject><subject>Humans</subject><subject>Liposomes</subject><subject>Liposomes - chemistry</subject><subject>Microscopy, Confocal</subject><subject>Microscopy, Electron</subject><subject>Microscopy, Electron, Transmission</subject><subject>Nanoconjugates - chemistry</subject><subject>Nanoparticle</subject><subject>Peptides - chemistry</subject><subject>Rats</subject><subject>RNA Interference</subject><subject>RNA, Small Interfering - administration & dosage</subject><subject>RNA, Small Interfering - chemistry</subject><subject>siRNA delivery</subject><subject>Targeting</subject><issn>0142-9612</issn><issn>1878-5905</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2011</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNkU1v1DAQhi1ERbeFv4AiLpwSxmM7HxyQqi0FpAqkAmfLsSfISxIHO1t1_z2JtiDUSzmNrHneGesZxl5xKDjw8s2uaH0YzEzRmz4VCJwXoApAfMI2vK7qXDWgnrINcIl5U3I8ZWcp7WB5g8Rn7BR5ibJUsGHbG7I0zSHms4k_aCaX9X4KKQyUT0vDO8pGMwYbhqmnO0pZF2KW_M3ni8xR728pHp6zk275CL24r-fs-9X7b9uP-fWXD5-2F9e5VQLn3JoWjYKuc0I1jbWyRatsLRuLrjbSdaV0VeNUbVC0ggwaWQvelNRBZYSR4py9Ps6dYvi1pzTrwSdLfW9GCvuk61oAlrISj5OVAlU1Ehby7ZG0MaQUqdNT9IOJB81Br7b1Tv9rW6-2NSi92F7CL-_X7NuB3N_oH70LcHkEaNFy6ynqZD2NlpyPZGftgv-_Pe8ejLG9H701_U86UNqFfRzXDNcJNeiv693Xs3MOoCRH8RvlQ60G</recordid><startdate>20110901</startdate><enddate>20110901</enddate><creator>Tagalakis, Aristides D</creator><creator>He, Lin</creator><creator>Saraiva, Luisa</creator><creator>Gustafsson, Kenth T</creator><creator>Hart, Stephen L</creator><general>Elsevier Ltd</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>7X8</scope><scope>7QO</scope><scope>7TM</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope></search><sort><creationdate>20110901</creationdate><title>Receptor-targeted liposome-peptide nanocomplexes for siRNA delivery</title><author>Tagalakis, Aristides D ; He, Lin ; Saraiva, Luisa ; Gustafsson, Kenth T ; Hart, Stephen L</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c532t-cab2a50ffd3599cc4b2c5c849c2d8a4df64d79d58a23b3ea2a483196ef07a3a43</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2011</creationdate><topic>Advanced Basic Science</topic><topic>Animals</topic><topic>Cell Line</topic><topic>Cell Line, Tumor</topic><topic>Cell Proliferation</topic><topic>Dentistry</topic><topic>Gene silencing</topic><topic>Gene Silencing - physiology</topic><topic>Heparin - chemistry</topic><topic>Humans</topic><topic>Liposomes</topic><topic>Liposomes - chemistry</topic><topic>Microscopy, Confocal</topic><topic>Microscopy, Electron</topic><topic>Microscopy, Electron, Transmission</topic><topic>Nanoconjugates - chemistry</topic><topic>Nanoparticle</topic><topic>Peptides - chemistry</topic><topic>Rats</topic><topic>RNA Interference</topic><topic>RNA, Small Interfering - administration & dosage</topic><topic>RNA, Small Interfering - chemistry</topic><topic>siRNA delivery</topic><topic>Targeting</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Tagalakis, Aristides D</creatorcontrib><creatorcontrib>He, Lin</creatorcontrib><creatorcontrib>Saraiva, Luisa</creatorcontrib><creatorcontrib>Gustafsson, Kenth T</creatorcontrib><creatorcontrib>Hart, Stephen L</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</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><jtitle>Biomaterials</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Tagalakis, Aristides D</au><au>He, Lin</au><au>Saraiva, Luisa</au><au>Gustafsson, Kenth T</au><au>Hart, Stephen L</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Receptor-targeted liposome-peptide nanocomplexes for siRNA delivery</atitle><jtitle>Biomaterials</jtitle><addtitle>Biomaterials</addtitle><date>2011-09-01</date><risdate>2011</risdate><volume>32</volume><issue>26</issue><spage>6302</spage><epage>6315</epage><pages>6302-6315</pages><issn>0142-9612</issn><eissn>1878-5905</eissn><abstract>Abstract RNA interference induced by double-stranded, small interfering RNA (siRNA) molecules has attracted great attention as a genetic therapeutic approach. Despite major advances in this field, new nanoparticle formulations are required for in vivo delivery of siRNA, particularly for tissue-specific delivery of siRNA reagents. We have developed and optimized LYR nanocomplex formulations for siRNA delivery that consist of a liposome (DOTMA/DOPE; L) and a targeting peptide (K16 GACYGLPHKFCG; Y) which self-assemble on mixing at optimal ratios with siRNA (R). Biophysical measurements indicated that LYR nanocomplexes were strongly cationic, mainly spherical particles of less than 100 nm. These formulations packaged and protected siRNA on incubation with RNAseA with >90% intact siRNA recovery. In addition, intact siRNA was recovered from LYRs upon heparin treatment. A critical synergy was observed between the lipid and peptide components for LYR particle stability and transfection efficiency. To evaluate targeting, transfections were compared with non-targeted formulations containing K16 with no targeting ligand. Gene knockdown efficiencies with targeted formulations were more than two-fold better in all cell lines tested ( p < 0.01). LYR formulations with liposomes containing DOTMA, which has an 18-carbon (C18) alkyl tail, were significantly better in silencing than formulations containing cationic lipids with shorter alkyl tails. LYRs with siRNA against endogenous luciferase and GAPDH were successful in silencing these genes in 3 cell lines (1HAEo- human airway epithelial, B104 rat neuroblastoma, Neuro2A-Luc mouse neuroblastoma) in vitro with 80% efficiency, similar in efficiency to Lipofectamine 2000. Confocal microscopy analysis with LYRs containing fluorescently labelled siRNA (Cy3) showed that the siRNA was located in the perinuclear region of the cytoplasm, where the RNA-induced silencing complex (RISC) is likely to be found. The LYR formulations may have applications for the further development of siRNA-based therapeutics.</abstract><cop>Netherlands</cop><pub>Elsevier Ltd</pub><pmid>21624650</pmid><doi>10.1016/j.biomaterials.2011.05.022</doi><tpages>14</tpages></addata></record> |
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| subjects | Advanced Basic Science Animals Cell Line Cell Line, Tumor Cell Proliferation Dentistry Gene silencing Gene Silencing - physiology Heparin - chemistry Humans Liposomes Liposomes - chemistry Microscopy, Confocal Microscopy, Electron Microscopy, Electron, Transmission Nanoconjugates - chemistry Nanoparticle Peptides - chemistry Rats RNA Interference RNA, Small Interfering - administration & dosage RNA, Small Interfering - chemistry siRNA delivery Targeting |
| title | Receptor-targeted liposome-peptide nanocomplexes for siRNA delivery |
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