Early-stage development of novel cyclodextrin-siRNA nanocomplexes allows for successful postnebulization transfection of bronchial epithelial cells
Successful delivery of small interfering RNA (siRNA) to the lungs remains hampered by poor intracellular delivery, vector-mediated cytotoxicity, and an inability to withstand nebulization. Recently, a novel cyclodextrin (CD), SC12CDClickpropylamine, consisting of distinct lipophilic and cationic sub...
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| Veröffentlicht in: | Journal of aerosol medicine 2014-12, Vol.27 (6), p.466-477 |
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| creator | Hibbitts, A O'Mahony, A M Forde, E Nolan, L Ogier, J Desgranges, S Darcy, R MacLoughlin, R O'Driscoll, C M Cryan, S A |
| description | Successful delivery of small interfering RNA (siRNA) to the lungs remains hampered by poor intracellular delivery, vector-mediated cytotoxicity, and an inability to withstand nebulization. Recently, a novel cyclodextrin (CD), SC12CDClickpropylamine, consisting of distinct lipophilic and cationic subunits, has been shown to transfect a number of cell types. However, the suitability of this vector for pulmonary siRNA delivery has not been assessed to date. To address this, a series of high-content analysis (HCA) and postnebulization assays were devised to determine the potential for CD-siRNA delivery to the lungs.
SC12CDClickpropylamine-siRNA mass ratios (MRs) were examined for size and zeta potential. In-depth analysis of nanocomplex uptake and toxicity in Calu-3 bronchial epithelial cells was examined using IN Cell(®) HCA assays. Nebulized SC12CDClickpropylamine nanocomplexes were assessed for volumetric median diameter (VMD) and fine particle fraction (FPF) and compared with saline controls. Finally, postnebulization stability was determined by comparing luciferase knockdown elicited by SC12CDClickpropylamine nanocomplexes before and after nebulization.
SC12CDClickpropylamine-siRNA complexation formed cationic nanocomplexes of ≤200 nm in size depending on the medium and led to significantly higher levels of siRNA associated with Calu-3 cells compared with RNAiFect-siRNA-treated cells at all MRs (p |
| doi_str_mv | 10.1089/jamp.2013.1045 |
| format | Article |
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SC12CDClickpropylamine-siRNA mass ratios (MRs) were examined for size and zeta potential. In-depth analysis of nanocomplex uptake and toxicity in Calu-3 bronchial epithelial cells was examined using IN Cell(®) HCA assays. Nebulized SC12CDClickpropylamine nanocomplexes were assessed for volumetric median diameter (VMD) and fine particle fraction (FPF) and compared with saline controls. Finally, postnebulization stability was determined by comparing luciferase knockdown elicited by SC12CDClickpropylamine nanocomplexes before and after nebulization.
SC12CDClickpropylamine-siRNA complexation formed cationic nanocomplexes of ≤200 nm in size depending on the medium and led to significantly higher levels of siRNA associated with Calu-3 cells compared with RNAiFect-siRNA-treated cells at all MRs (p<0.001, n=3×4), with evidence of toxicity only at MRs 50-100. Nebulization of SC12CDClickpropylamine nanocomplexes using the Aeroneb(®) Pro resulted in VMDs of ∼4 μm and FPFs of ∼57% at all MRs. SC12CDClickpropylamine-siRNA-mediated luciferase knockdown was found to be 39.8±3.6% at MR=20 before and 35.6±4.55% after nebulization, comparable to results observed using unnebulized commercial transfection reagent, RNAiFect.
SC12CDClickpropylamine nanocomplexes can be effectively nebulized for pulmonary delivery of siRNA using Aeroneb technology to mediate knockdown in airway cells. To the best of our knowledge, this is the first study examining the suitability of SC12CDClickpropylamine-siRNA nanocomplexes for pulmonary delivery. Furthermore, this work provides an integrated nanomedicine-device combination for future in vitro and in vivo preclinical and clinical studies of inhaled siRNA therapeutics.</description><identifier>ISSN: 1941-2711</identifier><identifier>EISSN: 1941-2703</identifier><identifier>DOI: 10.1089/jamp.2013.1045</identifier><identifier>PMID: 24665866</identifier><language>eng</language><publisher>United States: Mary Ann Liebert, Inc</publisher><subject>Administration, Inhalation ; beta-Cyclodextrins - administration & dosage ; beta-Cyclodextrins - chemistry ; beta-Cyclodextrins - toxicity ; Cell Line ; Gene Expression Regulation ; Genes, Reporter ; Health technology assessment ; High-Throughput Screening Assays ; Humans ; Luciferases - genetics ; Luciferases - metabolism ; Nanoparticles ; Nebulizers and Vaporizers ; Particle Size ; RNA Interference ; RNA, Small Interfering - administration & dosage ; RNA, Small Interfering - chemistry ; RNA, Small Interfering - genetics ; RNA, Small Interfering - metabolism ; Time Factors ; Transfection - methods</subject><ispartof>Journal of aerosol medicine, 2014-12, Vol.27 (6), p.466-477</ispartof><rights>(©) Copyright 2014, Mary Ann Liebert, Inc.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c462t-8b1aa1401d8a13984fa453c07b2354b296a1c75f6ca76bff8b315c11017c78113</citedby><cites>FETCH-LOGICAL-c462t-8b1aa1401d8a13984fa453c07b2354b296a1c75f6ca76bff8b315c11017c78113</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24665866$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Hibbitts, A</creatorcontrib><creatorcontrib>O'Mahony, A M</creatorcontrib><creatorcontrib>Forde, E</creatorcontrib><creatorcontrib>Nolan, L</creatorcontrib><creatorcontrib>Ogier, J</creatorcontrib><creatorcontrib>Desgranges, S</creatorcontrib><creatorcontrib>Darcy, R</creatorcontrib><creatorcontrib>MacLoughlin, R</creatorcontrib><creatorcontrib>O'Driscoll, C M</creatorcontrib><creatorcontrib>Cryan, S A</creatorcontrib><title>Early-stage development of novel cyclodextrin-siRNA nanocomplexes allows for successful postnebulization transfection of bronchial epithelial cells</title><title>Journal of aerosol medicine</title><addtitle>J Aerosol Med Pulm Drug Deliv</addtitle><description>Successful delivery of small interfering RNA (siRNA) to the lungs remains hampered by poor intracellular delivery, vector-mediated cytotoxicity, and an inability to withstand nebulization. Recently, a novel cyclodextrin (CD), SC12CDClickpropylamine, consisting of distinct lipophilic and cationic subunits, has been shown to transfect a number of cell types. However, the suitability of this vector for pulmonary siRNA delivery has not been assessed to date. To address this, a series of high-content analysis (HCA) and postnebulization assays were devised to determine the potential for CD-siRNA delivery to the lungs.
SC12CDClickpropylamine-siRNA mass ratios (MRs) were examined for size and zeta potential. In-depth analysis of nanocomplex uptake and toxicity in Calu-3 bronchial epithelial cells was examined using IN Cell(®) HCA assays. Nebulized SC12CDClickpropylamine nanocomplexes were assessed for volumetric median diameter (VMD) and fine particle fraction (FPF) and compared with saline controls. Finally, postnebulization stability was determined by comparing luciferase knockdown elicited by SC12CDClickpropylamine nanocomplexes before and after nebulization.
SC12CDClickpropylamine-siRNA complexation formed cationic nanocomplexes of ≤200 nm in size depending on the medium and led to significantly higher levels of siRNA associated with Calu-3 cells compared with RNAiFect-siRNA-treated cells at all MRs (p<0.001, n=3×4), with evidence of toxicity only at MRs 50-100. Nebulization of SC12CDClickpropylamine nanocomplexes using the Aeroneb(®) Pro resulted in VMDs of ∼4 μm and FPFs of ∼57% at all MRs. SC12CDClickpropylamine-siRNA-mediated luciferase knockdown was found to be 39.8±3.6% at MR=20 before and 35.6±4.55% after nebulization, comparable to results observed using unnebulized commercial transfection reagent, RNAiFect.
SC12CDClickpropylamine nanocomplexes can be effectively nebulized for pulmonary delivery of siRNA using Aeroneb technology to mediate knockdown in airway cells. To the best of our knowledge, this is the first study examining the suitability of SC12CDClickpropylamine-siRNA nanocomplexes for pulmonary delivery. Furthermore, this work provides an integrated nanomedicine-device combination for future in vitro and in vivo preclinical and clinical studies of inhaled siRNA therapeutics.</description><subject>Administration, Inhalation</subject><subject>beta-Cyclodextrins - administration & dosage</subject><subject>beta-Cyclodextrins - chemistry</subject><subject>beta-Cyclodextrins - toxicity</subject><subject>Cell Line</subject><subject>Gene Expression Regulation</subject><subject>Genes, Reporter</subject><subject>Health technology assessment</subject><subject>High-Throughput Screening Assays</subject><subject>Humans</subject><subject>Luciferases - genetics</subject><subject>Luciferases - metabolism</subject><subject>Nanoparticles</subject><subject>Nebulizers and Vaporizers</subject><subject>Particle Size</subject><subject>RNA Interference</subject><subject>RNA, Small Interfering - administration & dosage</subject><subject>RNA, Small Interfering - chemistry</subject><subject>RNA, Small Interfering - genetics</subject><subject>RNA, Small Interfering - metabolism</subject><subject>Time Factors</subject><subject>Transfection - methods</subject><issn>1941-2711</issn><issn>1941-2703</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><recordid>eNqNkT1v1TAUhi0EoqWwMiJLLCy5-PgryVhV5UOqQEIwR46vTXPl2MHHgV7-Bn8Yh5YOTEw-r_T4lY8fQp4D2wHr-tcHMy87zkDUKNUDcgq9hIa3TDy8nwFOyBPEA2MapBaPyQmXWqtO61Py69LkcGywmK-O7t13F9Iyu1ho8jSmGqk92pD27qbkKTY4ffpwTqOJyaZ5Ce7GITUhpB9IfcoUV2sdol8DXRKW6MY1TD9NmVKkJZuI3tk_obaPOUV7PZlA3TKVaxe20boQ8Cl55E1A9-zuPCNf3lx-vnjXXH18-_7i_KqxUvPSdCMYA5LBvjMg-k56I5WwrB25UHLkvTZgW-W1Na0eve9GAcoCMGht2wGIM_LqtnfJ6dvqsAzzhNsLTHRpxQG0qv-kmer-AxWSty3XvKIv_0EPac2xLlIp3vdCgmKV2t1SNifE7Pyw5Gk2-TgAGzazw2Z22MwOm9l64cVd7TrObn-P_1UpfgPaQKHy</recordid><startdate>201412</startdate><enddate>201412</enddate><creator>Hibbitts, A</creator><creator>O'Mahony, A M</creator><creator>Forde, E</creator><creator>Nolan, L</creator><creator>Ogier, J</creator><creator>Desgranges, S</creator><creator>Darcy, R</creator><creator>MacLoughlin, R</creator><creator>O'Driscoll, C M</creator><creator>Cryan, S A</creator><general>Mary Ann Liebert, Inc</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>3V.</scope><scope>7T5</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>H94</scope><scope>K9.</scope><scope>M0S</scope><scope>M1P</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>7X8</scope><scope>7TM</scope></search><sort><creationdate>201412</creationdate><title>Early-stage development of novel cyclodextrin-siRNA nanocomplexes allows for successful postnebulization transfection of bronchial epithelial cells</title><author>Hibbitts, A ; 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Recently, a novel cyclodextrin (CD), SC12CDClickpropylamine, consisting of distinct lipophilic and cationic subunits, has been shown to transfect a number of cell types. However, the suitability of this vector for pulmonary siRNA delivery has not been assessed to date. To address this, a series of high-content analysis (HCA) and postnebulization assays were devised to determine the potential for CD-siRNA delivery to the lungs.
SC12CDClickpropylamine-siRNA mass ratios (MRs) were examined for size and zeta potential. In-depth analysis of nanocomplex uptake and toxicity in Calu-3 bronchial epithelial cells was examined using IN Cell(®) HCA assays. Nebulized SC12CDClickpropylamine nanocomplexes were assessed for volumetric median diameter (VMD) and fine particle fraction (FPF) and compared with saline controls. Finally, postnebulization stability was determined by comparing luciferase knockdown elicited by SC12CDClickpropylamine nanocomplexes before and after nebulization.
SC12CDClickpropylamine-siRNA complexation formed cationic nanocomplexes of ≤200 nm in size depending on the medium and led to significantly higher levels of siRNA associated with Calu-3 cells compared with RNAiFect-siRNA-treated cells at all MRs (p<0.001, n=3×4), with evidence of toxicity only at MRs 50-100. Nebulization of SC12CDClickpropylamine nanocomplexes using the Aeroneb(®) Pro resulted in VMDs of ∼4 μm and FPFs of ∼57% at all MRs. SC12CDClickpropylamine-siRNA-mediated luciferase knockdown was found to be 39.8±3.6% at MR=20 before and 35.6±4.55% after nebulization, comparable to results observed using unnebulized commercial transfection reagent, RNAiFect.
SC12CDClickpropylamine nanocomplexes can be effectively nebulized for pulmonary delivery of siRNA using Aeroneb technology to mediate knockdown in airway cells. To the best of our knowledge, this is the first study examining the suitability of SC12CDClickpropylamine-siRNA nanocomplexes for pulmonary delivery. Furthermore, this work provides an integrated nanomedicine-device combination for future in vitro and in vivo preclinical and clinical studies of inhaled siRNA therapeutics.</abstract><cop>United States</cop><pub>Mary Ann Liebert, Inc</pub><pmid>24665866</pmid><doi>10.1089/jamp.2013.1045</doi><tpages>12</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Administration, Inhalation beta-Cyclodextrins - administration & dosage beta-Cyclodextrins - chemistry beta-Cyclodextrins - toxicity Cell Line Gene Expression Regulation Genes, Reporter Health technology assessment High-Throughput Screening Assays Humans Luciferases - genetics Luciferases - metabolism Nanoparticles Nebulizers and Vaporizers Particle Size RNA Interference RNA, Small Interfering - administration & dosage RNA, Small Interfering - chemistry RNA, Small Interfering - genetics RNA, Small Interfering - metabolism Time Factors Transfection - methods |
| title | Early-stage development of novel cyclodextrin-siRNA nanocomplexes allows for successful postnebulization transfection of bronchial epithelial cells |
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