Anionic nanoparticles enable the oral delivery of proteins by enhancing intestinal permeability
The oral delivery of bioactive peptides and proteins is prevented by the intestinal epithelial barrier, in which intercellular tight junction complexes block the uptake of macromolecules. Here we show that anionic nanoparticles induce tight junction relaxation, increasing intestinal permeability and...
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| Veröffentlicht in: | Nature biomedical engineering 2020-01, Vol.4 (1), p.84-96 |
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| creator | Lamson, Nicholas G. Berger, Adrian Fein, Katherine C. Whitehead, Kathryn A. |
| description | The oral delivery of bioactive peptides and proteins is prevented by the intestinal epithelial barrier, in which intercellular tight junction complexes block the uptake of macromolecules. Here we show that anionic nanoparticles induce tight junction relaxation, increasing intestinal permeability and enabling the oral delivery of proteins. This permeation-enhancing effect is a function of nanoparticle size and charge, with smaller (≤ 200 nm) and more negative particles (such as silica) conferring enhanced permeability. In healthy mice, silica nanoparticles enabled the oral delivery of insulin and exenatide, with 10 U kg
−1
orally delivered insulin sustaining hypoglycaemia for a few hours longer than a 1 U kg
−1
dose of subcutaneously injected insulin. In healthy, hyperglycaemic and diabetic mice, the oral delivery of 10 U kg
−1
insulin led to a dose-adjusted bioactivity of, respectively, 35%, 29% and 23% that of the subcutaneous injection of 1 U kg
−1
insulin. The permeation-enhancing effect of the nanoparticles was reversible, non-toxic, and attributable to the binding to integrins on the surface of epithelial cells.
Anionic nanoparticles increase intestinal permeability and enable the oral delivery of proteins, as shown with the delivery of insulin in healthy, hyperglycaemic, and diabetic mice. |
| doi_str_mv | 10.1038/s41551-019-0465-5 |
| format | Article |
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−1
orally delivered insulin sustaining hypoglycaemia for a few hours longer than a 1 U kg
−1
dose of subcutaneously injected insulin. In healthy, hyperglycaemic and diabetic mice, the oral delivery of 10 U kg
−1
insulin led to a dose-adjusted bioactivity of, respectively, 35%, 29% and 23% that of the subcutaneous injection of 1 U kg
−1
insulin. The permeation-enhancing effect of the nanoparticles was reversible, non-toxic, and attributable to the binding to integrins on the surface of epithelial cells.
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−1
orally delivered insulin sustaining hypoglycaemia for a few hours longer than a 1 U kg
−1
dose of subcutaneously injected insulin. In healthy, hyperglycaemic and diabetic mice, the oral delivery of 10 U kg
−1
insulin led to a dose-adjusted bioactivity of, respectively, 35%, 29% and 23% that of the subcutaneous injection of 1 U kg
−1
insulin. The permeation-enhancing effect of the nanoparticles was reversible, non-toxic, and attributable to the binding to integrins on the surface of epithelial cells.
Anionic nanoparticles increase intestinal permeability and enable the oral delivery of proteins, as shown with the delivery of insulin in healthy, hyperglycaemic, and diabetic mice.</description><subject>13/1</subject><subject>14/19</subject><subject>631/61/2297</subject><subject>639/166/985</subject><subject>639/925/350</subject><subject>64</subject><subject>64/60</subject><subject>82</subject><subject>82/80</subject><subject>Administration, Oral</subject><subject>Animals</subject><subject>Biocompatibility</subject><subject>Biological activity</subject><subject>Biomedical and Life Sciences</subject><subject>Biomedical Engineering/Biotechnology</subject><subject>Biomedicine</subject><subject>Cell Line</subject><subject>Cell Membrane Permeability - drug effects</subject><subject>Diabetes</subject><subject>Diabetes mellitus</subject><subject>Diabetes Mellitus, Type 1 - drug therapy</subject><subject>Drug Delivery Systems</subject><subject>Epithelial cells</subject><subject>Exenatide - administration & dosage</subject><subject>Hypoglycemia</subject><subject>Insulin</subject><subject>Insulin - administration & dosage</subject><subject>Integrins</subject><subject>Intestinal Mucosa - drug effects</subject><subject>Intestinal Mucosa - metabolism</subject><subject>Intestine</subject><subject>Macromolecules</subject><subject>Mice, Inbred C57BL</subject><subject>Nanoparticles</subject><subject>Nanoparticles - administration & dosage</subject><subject>Nanoparticles - chemistry</subject><subject>Particle Size</subject><subject>Penetration</subject><subject>Peptides</subject><subject>Permeability</subject><subject>Proteins</subject><subject>Silica</subject><subject>Silicon dioxide</subject><subject>Silicon Dioxide - administration & dosage</subject><subject>Tight Junctions - drug effects</subject><subject>Tight Junctions - metabolism</subject><issn>2157-846X</issn><issn>2157-846X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><recordid>eNp1kMtKAzEUhoMottQ-gBsJuB5NJreZZSneQHCj4C4kM2falGmmJlNh3t6UqZeNqxzId_7z8yF0SckNJay4jZwKQTNCy4xwKTJxgqY5FSoruHw__TNP0DzGDSGJZLxU4hxNGJWFJCSfIr3wrvOuwt74bmdC76oWIgZvbAu4XwPugmlxDa37hDDgrsG70PXgfMR2SNza-Mr5FXa-h9g7n-AdhC0Y61rXDxforDFthPnxnaG3-7vX5WP2_PLwtFw8ZxUvaJ-VTV2qvGxAEE5UJaiCknKR07qpSlYxktdFQ4QxUHNhoSFWKmuotJYJRVTNZuh6zE3tPvapid50-5DaRJ0zpaQkpeCJoiNVhS7GAI3eBbc1YdCU6INVPVrVyZU-WNUi7Vwdk_d2C_XPxrfDBOQjENOXX0H4Pf1_6heg3YN9</recordid><startdate>20200101</startdate><enddate>20200101</enddate><creator>Lamson, Nicholas G.</creator><creator>Berger, Adrian</creator><creator>Fein, Katherine C.</creator><creator>Whitehead, Kathryn A.</creator><general>Nature Publishing Group UK</general><general>Nature Publishing Group</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>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>ABJCF</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>GNUQQ</scope><scope>HCIFZ</scope><scope>L6V</scope><scope>LK8</scope><scope>M7P</scope><scope>M7S</scope><scope>P5Z</scope><scope>P62</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>PTHSS</scope><orcidid>https://orcid.org/0000-0002-0100-7824</orcidid></search><sort><creationdate>20200101</creationdate><title>Anionic nanoparticles enable the oral delivery of proteins by enhancing intestinal permeability</title><author>Lamson, Nicholas G. ; Berger, Adrian ; Fein, Katherine C. ; Whitehead, Kathryn A.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c481t-9fd9729fe50407c517e914521dfc93c302d8f05aaed45bef0b67ba16bb35707d3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>13/1</topic><topic>14/19</topic><topic>631/61/2297</topic><topic>639/166/985</topic><topic>639/925/350</topic><topic>64</topic><topic>64/60</topic><topic>82</topic><topic>82/80</topic><topic>Administration, Oral</topic><topic>Animals</topic><topic>Biocompatibility</topic><topic>Biological activity</topic><topic>Biomedical and Life Sciences</topic><topic>Biomedical Engineering/Biotechnology</topic><topic>Biomedicine</topic><topic>Cell Line</topic><topic>Cell Membrane Permeability - drug effects</topic><topic>Diabetes</topic><topic>Diabetes mellitus</topic><topic>Diabetes Mellitus, Type 1 - drug therapy</topic><topic>Drug Delivery Systems</topic><topic>Epithelial cells</topic><topic>Exenatide - administration & dosage</topic><topic>Hypoglycemia</topic><topic>Insulin</topic><topic>Insulin - administration & dosage</topic><topic>Integrins</topic><topic>Intestinal Mucosa - drug effects</topic><topic>Intestinal Mucosa - metabolism</topic><topic>Intestine</topic><topic>Macromolecules</topic><topic>Mice, Inbred C57BL</topic><topic>Nanoparticles</topic><topic>Nanoparticles - administration & dosage</topic><topic>Nanoparticles - chemistry</topic><topic>Particle Size</topic><topic>Penetration</topic><topic>Peptides</topic><topic>Permeability</topic><topic>Proteins</topic><topic>Silica</topic><topic>Silicon dioxide</topic><topic>Silicon Dioxide - administration & dosage</topic><topic>Tight Junctions - drug effects</topic><topic>Tight Junctions - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Lamson, Nicholas G.</creatorcontrib><creatorcontrib>Berger, Adrian</creatorcontrib><creatorcontrib>Fein, Katherine C.</creatorcontrib><creatorcontrib>Whitehead, Kathryn A.</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Technology Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Materials Science & Engineering Collection</collection><collection>ProQuest Central UK/Ireland</collection><collection>Advanced Technologies & Aerospace Collection</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Technology Collection</collection><collection>Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>ProQuest Central Student</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Engineering Collection</collection><collection>ProQuest Biological Science Collection</collection><collection>Biological Science Database</collection><collection>Engineering Database</collection><collection>Advanced Technologies & Aerospace Database</collection><collection>ProQuest Advanced Technologies & Aerospace Collection</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>Engineering Collection</collection><jtitle>Nature biomedical engineering</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Lamson, Nicholas G.</au><au>Berger, Adrian</au><au>Fein, Katherine C.</au><au>Whitehead, Kathryn A.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Anionic nanoparticles enable the oral delivery of proteins by enhancing intestinal permeability</atitle><jtitle>Nature biomedical engineering</jtitle><stitle>Nat Biomed Eng</stitle><addtitle>Nat Biomed Eng</addtitle><date>2020-01-01</date><risdate>2020</risdate><volume>4</volume><issue>1</issue><spage>84</spage><epage>96</epage><pages>84-96</pages><issn>2157-846X</issn><eissn>2157-846X</eissn><abstract>The oral delivery of bioactive peptides and proteins is prevented by the intestinal epithelial barrier, in which intercellular tight junction complexes block the uptake of macromolecules. Here we show that anionic nanoparticles induce tight junction relaxation, increasing intestinal permeability and enabling the oral delivery of proteins. This permeation-enhancing effect is a function of nanoparticle size and charge, with smaller (≤ 200 nm) and more negative particles (such as silica) conferring enhanced permeability. In healthy mice, silica nanoparticles enabled the oral delivery of insulin and exenatide, with 10 U kg
−1
orally delivered insulin sustaining hypoglycaemia for a few hours longer than a 1 U kg
−1
dose of subcutaneously injected insulin. In healthy, hyperglycaemic and diabetic mice, the oral delivery of 10 U kg
−1
insulin led to a dose-adjusted bioactivity of, respectively, 35%, 29% and 23% that of the subcutaneous injection of 1 U kg
−1
insulin. The permeation-enhancing effect of the nanoparticles was reversible, non-toxic, and attributable to the binding to integrins on the surface of epithelial cells.
Anionic nanoparticles increase intestinal permeability and enable the oral delivery of proteins, as shown with the delivery of insulin in healthy, hyperglycaemic, and diabetic mice.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>31686002</pmid><doi>10.1038/s41551-019-0465-5</doi><tpages>13</tpages><orcidid>https://orcid.org/0000-0002-0100-7824</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | 13/1 14/19 631/61/2297 639/166/985 639/925/350 64 64/60 82 82/80 Administration, Oral Animals Biocompatibility Biological activity Biomedical and Life Sciences Biomedical Engineering/Biotechnology Biomedicine Cell Line Cell Membrane Permeability - drug effects Diabetes Diabetes mellitus Diabetes Mellitus, Type 1 - drug therapy Drug Delivery Systems Epithelial cells Exenatide - administration & dosage Hypoglycemia Insulin Insulin - administration & dosage Integrins Intestinal Mucosa - drug effects Intestinal Mucosa - metabolism Intestine Macromolecules Mice, Inbred C57BL Nanoparticles Nanoparticles - administration & dosage Nanoparticles - chemistry Particle Size Penetration Peptides Permeability Proteins Silica Silicon dioxide Silicon Dioxide - administration & dosage Tight Junctions - drug effects Tight Junctions - metabolism |
| title | Anionic nanoparticles enable the oral delivery of proteins by enhancing intestinal permeability |
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