PECAM-1 directed re-targeting of exogenous mRNA providing two orders of magnitude enhancement of vascular delivery and expression in lungs independent of apolipoprotein E-mediated uptake
Systemic administration of lipid nanoparticle (LNP)-encapsulated messenger RNA (mRNA) leads predominantly to hepatic uptake and expression. Here, we conjugated nucleoside-modified mRNA-LNPs with antibodies (Abs) specific to vascular cell adhesion molecule, PECAM-1. Systemic (intravenous) administrat...
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| Veröffentlicht in: | Journal of controlled release 2018-12, Vol.291, p.106-115 |
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| creator | Parhiz, Hamideh Shuvaev, Vladimir V. Pardi, Norbert Khoshnejad, Makan Kiseleva, Raisa Yu Brenner, Jacob S. Uhler, Thomas Tuyishime, Steven Mui, Barbara L. Tam, Ying K. Madden, Thomas D. Hope, Michael J. Weissman, Drew Muzykantov, Vladimir R. |
| description | Systemic administration of lipid nanoparticle (LNP)-encapsulated messenger RNA (mRNA) leads predominantly to hepatic uptake and expression. Here, we conjugated nucleoside-modified mRNA-LNPs with antibodies (Abs) specific to vascular cell adhesion molecule, PECAM-1. Systemic (intravenous) administration of Ab/LNP-mRNAs resulted in profound inhibition of hepatic uptake concomitantly with ~200-fold and 25-fold elevation of mRNA delivery and protein expression in the lungs compared to non-targeted counterparts. Unlike hepatic delivery of LNP-mRNA, Ab/LNP-mRNA is independent of apolipoprotein E. Vascular re-targeting of mRNA represents a promising, powerful, and unique approach for novel experimental and clinical interventions in organs of interest other than liver.
[Display omitted]
•Robust pulmonary targeting of mRNA was achieved by endothelial targeted anti-PECAM/LNP-mRNA nanoparticles.•Delivery of targeted Anti-PECAM/LNP-mRNA nanoparticles is independent of apolipoprotein E pathway.•Around 200-fold elevation in pulmonary mRNA expression was reached upon IV administration of targeted nanoparticles.•Rapid, transient, and specific protein expression from reporter mRNA was observed, with limited off-target biodistribution. |
| doi_str_mv | 10.1016/j.jconrel.2018.10.015 |
| format | Article |
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[Display omitted]
•Robust pulmonary targeting of mRNA was achieved by endothelial targeted anti-PECAM/LNP-mRNA nanoparticles.•Delivery of targeted Anti-PECAM/LNP-mRNA nanoparticles is independent of apolipoprotein E pathway.•Around 200-fold elevation in pulmonary mRNA expression was reached upon IV administration of targeted nanoparticles.•Rapid, transient, and specific protein expression from reporter mRNA was observed, with limited off-target biodistribution.</description><identifier>ISSN: 0168-3659</identifier><identifier>EISSN: 1873-4995</identifier><identifier>DOI: 10.1016/j.jconrel.2018.10.015</identifier><identifier>PMID: 30336167</identifier><language>eng</language><publisher>Netherlands: Elsevier B.V</publisher><subject>Administration, Intravenous ; Animals ; antibodies ; Apolipoprotein E ; Apolipoproteins E - metabolism ; Cell Line ; Drug Carriers - metabolism ; Drug Delivery Systems - methods ; encapsulation ; Endothelial targeting ; Endothelium, Vascular - metabolism ; Human Umbilical Vein Endothelial Cells ; Humans ; Immunoconjugates - metabolism ; Inflammation ; intravenous injection ; liver ; lungs ; messenger RNA ; Mice, Inbred C57BL ; mRNA delivery ; nanoparticles ; Nanoparticles - metabolism ; Platelet Endothelial Cell Adhesion Molecule-1 - metabolism ; protein synthesis ; RNA, Messenger - administration & dosage ; RNA, Messenger - pharmacokinetics ; Tissue Distribution ; vascular cell adhesion molecules ; Vascular targeting</subject><ispartof>Journal of controlled release, 2018-12, Vol.291, p.106-115</ispartof><rights>2018</rights><rights>Copyright © 2018. Published by Elsevier B.V.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c618t-b78ec4da589656e6b3dd9b4e110c290f57da15cceba92a5aff323880e51c1d53</citedby><cites>FETCH-LOGICAL-c618t-b78ec4da589656e6b3dd9b4e110c290f57da15cceba92a5aff323880e51c1d53</cites><orcidid>0000-0001-5143-304X</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0168365918305868$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>230,314,776,780,881,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/30336167$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Parhiz, Hamideh</creatorcontrib><creatorcontrib>Shuvaev, Vladimir V.</creatorcontrib><creatorcontrib>Pardi, Norbert</creatorcontrib><creatorcontrib>Khoshnejad, Makan</creatorcontrib><creatorcontrib>Kiseleva, Raisa Yu</creatorcontrib><creatorcontrib>Brenner, Jacob S.</creatorcontrib><creatorcontrib>Uhler, Thomas</creatorcontrib><creatorcontrib>Tuyishime, Steven</creatorcontrib><creatorcontrib>Mui, Barbara L.</creatorcontrib><creatorcontrib>Tam, Ying K.</creatorcontrib><creatorcontrib>Madden, Thomas D.</creatorcontrib><creatorcontrib>Hope, Michael J.</creatorcontrib><creatorcontrib>Weissman, Drew</creatorcontrib><creatorcontrib>Muzykantov, Vladimir R.</creatorcontrib><title>PECAM-1 directed re-targeting of exogenous mRNA providing two orders of magnitude enhancement of vascular delivery and expression in lungs independent of apolipoprotein E-mediated uptake</title><title>Journal of controlled release</title><addtitle>J Control Release</addtitle><description>Systemic administration of lipid nanoparticle (LNP)-encapsulated messenger RNA (mRNA) leads predominantly to hepatic uptake and expression. Here, we conjugated nucleoside-modified mRNA-LNPs with antibodies (Abs) specific to vascular cell adhesion molecule, PECAM-1. Systemic (intravenous) administration of Ab/LNP-mRNAs resulted in profound inhibition of hepatic uptake concomitantly with ~200-fold and 25-fold elevation of mRNA delivery and protein expression in the lungs compared to non-targeted counterparts. Unlike hepatic delivery of LNP-mRNA, Ab/LNP-mRNA is independent of apolipoprotein E. Vascular re-targeting of mRNA represents a promising, powerful, and unique approach for novel experimental and clinical interventions in organs of interest other than liver.
[Display omitted]
•Robust pulmonary targeting of mRNA was achieved by endothelial targeted anti-PECAM/LNP-mRNA nanoparticles.•Delivery of targeted Anti-PECAM/LNP-mRNA nanoparticles is independent of apolipoprotein E pathway.•Around 200-fold elevation in pulmonary mRNA expression was reached upon IV administration of targeted nanoparticles.•Rapid, transient, and specific protein expression from reporter mRNA was observed, with limited off-target biodistribution.</description><subject>Administration, Intravenous</subject><subject>Animals</subject><subject>antibodies</subject><subject>Apolipoprotein E</subject><subject>Apolipoproteins E - metabolism</subject><subject>Cell Line</subject><subject>Drug Carriers - metabolism</subject><subject>Drug Delivery Systems - methods</subject><subject>encapsulation</subject><subject>Endothelial targeting</subject><subject>Endothelium, Vascular - metabolism</subject><subject>Human Umbilical Vein Endothelial Cells</subject><subject>Humans</subject><subject>Immunoconjugates - metabolism</subject><subject>Inflammation</subject><subject>intravenous injection</subject><subject>liver</subject><subject>lungs</subject><subject>messenger RNA</subject><subject>Mice, Inbred C57BL</subject><subject>mRNA delivery</subject><subject>nanoparticles</subject><subject>Nanoparticles - metabolism</subject><subject>Platelet Endothelial Cell Adhesion Molecule-1 - metabolism</subject><subject>protein synthesis</subject><subject>RNA, Messenger - administration & dosage</subject><subject>RNA, Messenger - pharmacokinetics</subject><subject>Tissue Distribution</subject><subject>vascular cell adhesion molecules</subject><subject>Vascular targeting</subject><issn>0168-3659</issn><issn>1873-4995</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkd-O1CAUxhujccfVR9Bw6U1HKANtbzSTyaibrH9i9p5QOO0ytlCB1t1X8-mk6bjRK2-AnPOd73zhl2UvCd4STPib0_aknPXQbwtMqlTbYsIeZRtSlTTf1TV7nG2SrsopZ_VF9iyEE8aY0V35NLugmFJOeLnJfn09HvafcoK08aAiaOQhj9J3EI3tkGsR3LkOrJsCGr593qPRu9nopRd_OuS8Bh8W2SA7a-KkAYG9lVbBADYujVkGNfXSIw29mcHfI2l1ch09hGCcRcaifrJdSA8NI6RjHZSj683o0sIISXPMB9BGLhGnMcrv8Dx70so-wIvzfZndvD_eHD7m118-XB3217nipIp5U1agdlqyquaMA2-o1nWzA0KwKmrcslJLwpSCRtaFZLJtaUGrCgMjimhGL7O3q-04NSmBSum87MXozSD9vXDSiH871tyKzs2C78qS14vB67OBdz8mCFEMJijoe2khfasoSFUzVhPCk5StUuVdCB7ahzUEiwW7OIkzdrFgX8oJe5p79XfGh6k_nJPg3SqA9FGzAS-CMpAordiFduY_K34D3vzH5g</recordid><startdate>20181210</startdate><enddate>20181210</enddate><creator>Parhiz, Hamideh</creator><creator>Shuvaev, Vladimir V.</creator><creator>Pardi, Norbert</creator><creator>Khoshnejad, Makan</creator><creator>Kiseleva, Raisa Yu</creator><creator>Brenner, Jacob S.</creator><creator>Uhler, Thomas</creator><creator>Tuyishime, Steven</creator><creator>Mui, Barbara L.</creator><creator>Tam, Ying K.</creator><creator>Madden, Thomas D.</creator><creator>Hope, Michael J.</creator><creator>Weissman, Drew</creator><creator>Muzykantov, Vladimir R.</creator><general>Elsevier B.V</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>7S9</scope><scope>L.6</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0001-5143-304X</orcidid></search><sort><creationdate>20181210</creationdate><title>PECAM-1 directed re-targeting of exogenous mRNA providing two orders of magnitude enhancement of vascular delivery and expression in lungs independent of apolipoprotein E-mediated uptake</title><author>Parhiz, Hamideh ; Shuvaev, Vladimir V. ; Pardi, Norbert ; Khoshnejad, Makan ; Kiseleva, Raisa Yu ; Brenner, Jacob S. ; Uhler, Thomas ; Tuyishime, Steven ; Mui, Barbara L. ; Tam, Ying K. ; Madden, Thomas D. ; Hope, Michael J. ; Weissman, Drew ; Muzykantov, Vladimir R.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c618t-b78ec4da589656e6b3dd9b4e110c290f57da15cceba92a5aff323880e51c1d53</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>Administration, Intravenous</topic><topic>Animals</topic><topic>antibodies</topic><topic>Apolipoprotein E</topic><topic>Apolipoproteins E - metabolism</topic><topic>Cell Line</topic><topic>Drug Carriers - metabolism</topic><topic>Drug Delivery Systems - methods</topic><topic>encapsulation</topic><topic>Endothelial targeting</topic><topic>Endothelium, Vascular - metabolism</topic><topic>Human Umbilical Vein Endothelial Cells</topic><topic>Humans</topic><topic>Immunoconjugates - metabolism</topic><topic>Inflammation</topic><topic>intravenous injection</topic><topic>liver</topic><topic>lungs</topic><topic>messenger RNA</topic><topic>Mice, Inbred C57BL</topic><topic>mRNA delivery</topic><topic>nanoparticles</topic><topic>Nanoparticles - metabolism</topic><topic>Platelet Endothelial Cell Adhesion Molecule-1 - metabolism</topic><topic>protein synthesis</topic><topic>RNA, Messenger - administration & dosage</topic><topic>RNA, Messenger - pharmacokinetics</topic><topic>Tissue Distribution</topic><topic>vascular cell adhesion molecules</topic><topic>Vascular targeting</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Parhiz, Hamideh</creatorcontrib><creatorcontrib>Shuvaev, Vladimir V.</creatorcontrib><creatorcontrib>Pardi, Norbert</creatorcontrib><creatorcontrib>Khoshnejad, Makan</creatorcontrib><creatorcontrib>Kiseleva, Raisa Yu</creatorcontrib><creatorcontrib>Brenner, Jacob S.</creatorcontrib><creatorcontrib>Uhler, Thomas</creatorcontrib><creatorcontrib>Tuyishime, Steven</creatorcontrib><creatorcontrib>Mui, Barbara L.</creatorcontrib><creatorcontrib>Tam, Ying K.</creatorcontrib><creatorcontrib>Madden, Thomas D.</creatorcontrib><creatorcontrib>Hope, Michael J.</creatorcontrib><creatorcontrib>Weissman, Drew</creatorcontrib><creatorcontrib>Muzykantov, Vladimir R.</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>AGRICOLA</collection><collection>AGRICOLA - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Journal of controlled release</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Parhiz, Hamideh</au><au>Shuvaev, Vladimir V.</au><au>Pardi, Norbert</au><au>Khoshnejad, Makan</au><au>Kiseleva, Raisa Yu</au><au>Brenner, Jacob S.</au><au>Uhler, Thomas</au><au>Tuyishime, Steven</au><au>Mui, Barbara L.</au><au>Tam, Ying K.</au><au>Madden, Thomas D.</au><au>Hope, Michael J.</au><au>Weissman, Drew</au><au>Muzykantov, Vladimir R.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>PECAM-1 directed re-targeting of exogenous mRNA providing two orders of magnitude enhancement of vascular delivery and expression in lungs independent of apolipoprotein E-mediated uptake</atitle><jtitle>Journal of controlled release</jtitle><addtitle>J Control Release</addtitle><date>2018-12-10</date><risdate>2018</risdate><volume>291</volume><spage>106</spage><epage>115</epage><pages>106-115</pages><issn>0168-3659</issn><eissn>1873-4995</eissn><abstract>Systemic administration of lipid nanoparticle (LNP)-encapsulated messenger RNA (mRNA) leads predominantly to hepatic uptake and expression. Here, we conjugated nucleoside-modified mRNA-LNPs with antibodies (Abs) specific to vascular cell adhesion molecule, PECAM-1. Systemic (intravenous) administration of Ab/LNP-mRNAs resulted in profound inhibition of hepatic uptake concomitantly with ~200-fold and 25-fold elevation of mRNA delivery and protein expression in the lungs compared to non-targeted counterparts. Unlike hepatic delivery of LNP-mRNA, Ab/LNP-mRNA is independent of apolipoprotein E. Vascular re-targeting of mRNA represents a promising, powerful, and unique approach for novel experimental and clinical interventions in organs of interest other than liver.
[Display omitted]
•Robust pulmonary targeting of mRNA was achieved by endothelial targeted anti-PECAM/LNP-mRNA nanoparticles.•Delivery of targeted Anti-PECAM/LNP-mRNA nanoparticles is independent of apolipoprotein E pathway.•Around 200-fold elevation in pulmonary mRNA expression was reached upon IV administration of targeted nanoparticles.•Rapid, transient, and specific protein expression from reporter mRNA was observed, with limited off-target biodistribution.</abstract><cop>Netherlands</cop><pub>Elsevier B.V</pub><pmid>30336167</pmid><doi>10.1016/j.jconrel.2018.10.015</doi><tpages>10</tpages><orcidid>https://orcid.org/0000-0001-5143-304X</orcidid><oa>free_for_read</oa></addata></record> |
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| ispartof | Journal of controlled release, 2018-12, Vol.291, p.106-115 |
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| source | MEDLINE; Elsevier ScienceDirect Journals |
| subjects | Administration, Intravenous Animals antibodies Apolipoprotein E Apolipoproteins E - metabolism Cell Line Drug Carriers - metabolism Drug Delivery Systems - methods encapsulation Endothelial targeting Endothelium, Vascular - metabolism Human Umbilical Vein Endothelial Cells Humans Immunoconjugates - metabolism Inflammation intravenous injection liver lungs messenger RNA Mice, Inbred C57BL mRNA delivery nanoparticles Nanoparticles - metabolism Platelet Endothelial Cell Adhesion Molecule-1 - metabolism protein synthesis RNA, Messenger - administration & dosage RNA, Messenger - pharmacokinetics Tissue Distribution vascular cell adhesion molecules Vascular targeting |
| title | PECAM-1 directed re-targeting of exogenous mRNA providing two orders of magnitude enhancement of vascular delivery and expression in lungs independent of apolipoprotein E-mediated uptake |
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