Modulation of Intercellular Junctions by Cyclic-ADT Peptides as a Method to Reversibly Increase Blood–Brain Barrier Permeability
It is challenging to deliver molecules to the brain for diagnosis and treatment of brain diseases. This is primarily because of the presence of the blood–brain barrier (BBB), which restricts the entry of many molecules into the brain. In this study, cyclic-ADT peptides (ADTC1, ADTC5, and ADTC6) have...
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| Veröffentlicht in: | Journal of pharmaceutical sciences 2015-03, Vol.104 (3), p.1065-1075 |
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| container_title | Journal of pharmaceutical sciences |
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| creator | Laksitorini, Marlyn D. Kiptoo, Paul K. On, Ngoc H. Thliveris, James A. Miller, Donald W. Siahaan, Teruna J. |
| description | It is challenging to deliver molecules to the brain for diagnosis and treatment of brain diseases. This is primarily because of the presence of the blood–brain barrier (BBB), which restricts the entry of many molecules into the brain. In this study, cyclic-ADT peptides (ADTC1, ADTC5, and ADTC6) have been shown to modify the BBB to enhance the delivery of marker molecules [e.g., 14C-mannitol, gadolinium-diethylenetriaminepentacetate (Gd-DTPA)] to the brain via the paracellular pathways of the BBB. The hypothesis is that these peptides modulate cadherin interactions in the adherens junctions of the vascular endothelial cells forming the BBB to increase paracellular drug permeation. In vitro studies indicated that ADTC5 had the best profile to inhibit adherens junction resealing in Madin–Darby canine kidney cell monolayers in a concentration-dependent manner (IC50=0.3mM) with a maximal response at 0.4mM. Under the current experimental conditions, ADTC5 improved the delivery of 14C-mannitol to the brain about twofold compared with the negative control in the in situ rat brain perfusion model. Furthermore, ADTC5 peptide increased in vivo delivery of Gd-DTPA to the brain of Balb/c mice when administered intravenously. In conclusion, ADTC5 has the potential to improve delivery of diagnostic and therapeutic agents to the brain. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association. |
| doi_str_mv | 10.1002/jps.24309 |
| format | Article |
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This is primarily because of the presence of the blood–brain barrier (BBB), which restricts the entry of many molecules into the brain. In this study, cyclic-ADT peptides (ADTC1, ADTC5, and ADTC6) have been shown to modify the BBB to enhance the delivery of marker molecules [e.g., 14C-mannitol, gadolinium-diethylenetriaminepentacetate (Gd-DTPA)] to the brain via the paracellular pathways of the BBB. The hypothesis is that these peptides modulate cadherin interactions in the adherens junctions of the vascular endothelial cells forming the BBB to increase paracellular drug permeation. In vitro studies indicated that ADTC5 had the best profile to inhibit adherens junction resealing in Madin–Darby canine kidney cell monolayers in a concentration-dependent manner (IC50=0.3mM) with a maximal response at 0.4mM. Under the current experimental conditions, ADTC5 improved the delivery of 14C-mannitol to the brain about twofold compared with the negative control in the in situ rat brain perfusion model. Furthermore, ADTC5 peptide increased in vivo delivery of Gd-DTPA to the brain of Balb/c mice when administered intravenously. In conclusion, ADTC5 has the potential to improve delivery of diagnostic and therapeutic agents to the brain. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association.</description><identifier>ISSN: 0022-3549</identifier><identifier>EISSN: 1520-6017</identifier><identifier>DOI: 10.1002/jps.24309</identifier><identifier>PMID: 25640479</identifier><identifier>CODEN: JPMSAE</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>absorption enhancer ; Animals ; Blood-Brain Barrier - drug effects ; Blood-Brain Barrier - metabolism ; blood–brain barrier ; Capillary Permeability - drug effects ; CNS ; Contrast Media - metabolism ; Dogs ; Dose-Response Relationship, Drug ; Drug Carriers ; Electric Impedance ; Endothelial Cells - drug effects ; Endothelial Cells - metabolism ; Female ; Gadolinium DTPA - metabolism ; imaging methods ; Injections, Intravenous ; Intercellular Junctions - drug effects ; Intercellular Junctions - metabolism ; Madin Darby Canine Kidney Cells ; Magnetic Resonance Imaging ; Mannitol - metabolism ; Mice, Inbred BALB C ; paracellular transport ; Peptides, Cyclic - administration & dosage ; Peptides, Cyclic - metabolism ; Peptides, Cyclic - pharmacology ; permeability ; permeation enhancers ; Polyethylene Glycols - metabolism ; Rats, Sprague-Dawley ; Time Factors</subject><ispartof>Journal of pharmaceutical sciences, 2015-03, Vol.104 (3), p.1065-1075</ispartof><rights>2014 Wiley Periodicals, Inc. and the American Pharmacists Association</rights><rights>2015 Wiley Periodicals, Inc. and the American Pharmacists Association</rights><rights>2015 Wiley Periodicals, Inc. and the American Pharmacists Association.</rights><rights>Copyright © 2015 Wiley Periodicals, Inc., A Wiley Company</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c5909-9f7f0667ff6001f77bdda5f3289c3233805af963ae6fd000bb252d6f49b5e20e3</citedby><cites>FETCH-LOGICAL-c5909-9f7f0667ff6001f77bdda5f3289c3233805af963ae6fd000bb252d6f49b5e20e3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1002%2Fjps.24309$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1002%2Fjps.24309$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>230,314,776,780,881,1411,27901,27902,45550,45551</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25640479$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Laksitorini, Marlyn D.</creatorcontrib><creatorcontrib>Kiptoo, Paul K.</creatorcontrib><creatorcontrib>On, Ngoc H.</creatorcontrib><creatorcontrib>Thliveris, James A.</creatorcontrib><creatorcontrib>Miller, Donald W.</creatorcontrib><creatorcontrib>Siahaan, Teruna J.</creatorcontrib><title>Modulation of Intercellular Junctions by Cyclic-ADT Peptides as a Method to Reversibly Increase Blood–Brain Barrier Permeability</title><title>Journal of pharmaceutical sciences</title><addtitle>J Pharm Sci</addtitle><description>It is challenging to deliver molecules to the brain for diagnosis and treatment of brain diseases. This is primarily because of the presence of the blood–brain barrier (BBB), which restricts the entry of many molecules into the brain. In this study, cyclic-ADT peptides (ADTC1, ADTC5, and ADTC6) have been shown to modify the BBB to enhance the delivery of marker molecules [e.g., 14C-mannitol, gadolinium-diethylenetriaminepentacetate (Gd-DTPA)] to the brain via the paracellular pathways of the BBB. The hypothesis is that these peptides modulate cadherin interactions in the adherens junctions of the vascular endothelial cells forming the BBB to increase paracellular drug permeation. In vitro studies indicated that ADTC5 had the best profile to inhibit adherens junction resealing in Madin–Darby canine kidney cell monolayers in a concentration-dependent manner (IC50=0.3mM) with a maximal response at 0.4mM. Under the current experimental conditions, ADTC5 improved the delivery of 14C-mannitol to the brain about twofold compared with the negative control in the in situ rat brain perfusion model. Furthermore, ADTC5 peptide increased in vivo delivery of Gd-DTPA to the brain of Balb/c mice when administered intravenously. In conclusion, ADTC5 has the potential to improve delivery of diagnostic and therapeutic agents to the brain. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association.</description><subject>absorption enhancer</subject><subject>Animals</subject><subject>Blood-Brain Barrier - drug effects</subject><subject>Blood-Brain Barrier - metabolism</subject><subject>blood–brain barrier</subject><subject>Capillary Permeability - drug effects</subject><subject>CNS</subject><subject>Contrast Media - metabolism</subject><subject>Dogs</subject><subject>Dose-Response Relationship, Drug</subject><subject>Drug Carriers</subject><subject>Electric Impedance</subject><subject>Endothelial Cells - drug effects</subject><subject>Endothelial Cells - metabolism</subject><subject>Female</subject><subject>Gadolinium DTPA - metabolism</subject><subject>imaging methods</subject><subject>Injections, Intravenous</subject><subject>Intercellular Junctions - drug effects</subject><subject>Intercellular Junctions - metabolism</subject><subject>Madin Darby Canine Kidney Cells</subject><subject>Magnetic Resonance Imaging</subject><subject>Mannitol - metabolism</subject><subject>Mice, Inbred BALB C</subject><subject>paracellular transport</subject><subject>Peptides, Cyclic - administration & dosage</subject><subject>Peptides, Cyclic - metabolism</subject><subject>Peptides, Cyclic - pharmacology</subject><subject>permeability</subject><subject>permeation enhancers</subject><subject>Polyethylene Glycols - metabolism</subject><subject>Rats, Sprague-Dawley</subject><subject>Time Factors</subject><issn>0022-3549</issn><issn>1520-6017</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkt1qFDEUgAdR7Fq98AUk4I1eTJtJJpnNjdBd_1paLFqvQyY5sVmyk20yszJ34iv4hj6JGbctKooQCOR8-Th_RfG4wgcVxuRwtUkHpKZY3ClmFSO45Lhq7hazHCMlZbXYKx6ktMIYc8zY_WKPMF7juhGz4utZMINXvQsdChYddz1EDd7nt4hOhk5PkYTaES1H7Z0uj15eoHPY9M5AQiofdAb9ZTCoD-g9bCEm1_oxi3QElQAtfAjm-5dvi6hchxYqRgcxG-IaVOu868eHxT2rfIJH1_d-8fH1q4vl2_L03Zvj5dFpqZnAohS2sZjzxlqOcWWbpjVGMUvJXGhKKJ1jpqzgVAG3JpfatoQRw20tWgYEA90vXuy8m6Fdg9HQ9VF5uYlureIog3Ly90jnLuWnsJV1XRM-b7Lg2bUghqsBUi_XLk3NUh2EIcmqYbTOjRXV_1HOWEMxZhP69A90FYbY5U5MVC0aQSjO1PMdpWNIKYK9zbvCcloCmZdA_lyCzD75tdBb8mbqGTjcAZ-dh_HfJnly_uFGSXc_IA9omycok3bQaTAugu6lCe4vifwANefPRw</recordid><startdate>201503</startdate><enddate>201503</enddate><creator>Laksitorini, Marlyn D.</creator><creator>Kiptoo, Paul K.</creator><creator>On, Ngoc H.</creator><creator>Thliveris, James A.</creator><creator>Miller, Donald W.</creator><creator>Siahaan, Teruna J.</creator><general>Elsevier Inc</general><general>Elsevier Limited</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>7QP</scope><scope>7QR</scope><scope>7TK</scope><scope>7U7</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>201503</creationdate><title>Modulation of Intercellular Junctions by Cyclic-ADT Peptides as a Method to Reversibly Increase Blood–Brain Barrier Permeability</title><author>Laksitorini, Marlyn D. ; Kiptoo, Paul K. ; On, Ngoc H. ; Thliveris, James A. ; Miller, Donald W. ; Siahaan, Teruna J.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c5909-9f7f0667ff6001f77bdda5f3289c3233805af963ae6fd000bb252d6f49b5e20e3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>absorption enhancer</topic><topic>Animals</topic><topic>Blood-Brain Barrier - drug effects</topic><topic>Blood-Brain Barrier - metabolism</topic><topic>blood–brain barrier</topic><topic>Capillary Permeability - drug effects</topic><topic>CNS</topic><topic>Contrast Media - metabolism</topic><topic>Dogs</topic><topic>Dose-Response Relationship, Drug</topic><topic>Drug Carriers</topic><topic>Electric Impedance</topic><topic>Endothelial Cells - drug effects</topic><topic>Endothelial Cells - metabolism</topic><topic>Female</topic><topic>Gadolinium DTPA - metabolism</topic><topic>imaging methods</topic><topic>Injections, Intravenous</topic><topic>Intercellular Junctions - drug effects</topic><topic>Intercellular Junctions - metabolism</topic><topic>Madin Darby Canine Kidney Cells</topic><topic>Magnetic Resonance Imaging</topic><topic>Mannitol - metabolism</topic><topic>Mice, Inbred BALB C</topic><topic>paracellular transport</topic><topic>Peptides, Cyclic - administration & dosage</topic><topic>Peptides, Cyclic - metabolism</topic><topic>Peptides, Cyclic - pharmacology</topic><topic>permeability</topic><topic>permeation enhancers</topic><topic>Polyethylene Glycols - metabolism</topic><topic>Rats, Sprague-Dawley</topic><topic>Time Factors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Laksitorini, Marlyn D.</creatorcontrib><creatorcontrib>Kiptoo, Paul K.</creatorcontrib><creatorcontrib>On, Ngoc H.</creatorcontrib><creatorcontrib>Thliveris, James A.</creatorcontrib><creatorcontrib>Miller, Donald W.</creatorcontrib><creatorcontrib>Siahaan, Teruna J.</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Biotechnology Research Abstracts</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Toxicology Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Journal of pharmaceutical sciences</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Laksitorini, Marlyn D.</au><au>Kiptoo, Paul K.</au><au>On, Ngoc H.</au><au>Thliveris, James A.</au><au>Miller, Donald W.</au><au>Siahaan, Teruna J.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Modulation of Intercellular Junctions by Cyclic-ADT Peptides as a Method to Reversibly Increase Blood–Brain Barrier Permeability</atitle><jtitle>Journal of pharmaceutical sciences</jtitle><addtitle>J Pharm Sci</addtitle><date>2015-03</date><risdate>2015</risdate><volume>104</volume><issue>3</issue><spage>1065</spage><epage>1075</epage><pages>1065-1075</pages><issn>0022-3549</issn><eissn>1520-6017</eissn><coden>JPMSAE</coden><abstract>It is challenging to deliver molecules to the brain for diagnosis and treatment of brain diseases. This is primarily because of the presence of the blood–brain barrier (BBB), which restricts the entry of many molecules into the brain. In this study, cyclic-ADT peptides (ADTC1, ADTC5, and ADTC6) have been shown to modify the BBB to enhance the delivery of marker molecules [e.g., 14C-mannitol, gadolinium-diethylenetriaminepentacetate (Gd-DTPA)] to the brain via the paracellular pathways of the BBB. The hypothesis is that these peptides modulate cadherin interactions in the adherens junctions of the vascular endothelial cells forming the BBB to increase paracellular drug permeation. In vitro studies indicated that ADTC5 had the best profile to inhibit adherens junction resealing in Madin–Darby canine kidney cell monolayers in a concentration-dependent manner (IC50=0.3mM) with a maximal response at 0.4mM. Under the current experimental conditions, ADTC5 improved the delivery of 14C-mannitol to the brain about twofold compared with the negative control in the in situ rat brain perfusion model. Furthermore, ADTC5 peptide increased in vivo delivery of Gd-DTPA to the brain of Balb/c mice when administered intravenously. In conclusion, ADTC5 has the potential to improve delivery of diagnostic and therapeutic agents to the brain. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>25640479</pmid><doi>10.1002/jps.24309</doi><tpages>11</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | absorption enhancer Animals Blood-Brain Barrier - drug effects Blood-Brain Barrier - metabolism blood–brain barrier Capillary Permeability - drug effects CNS Contrast Media - metabolism Dogs Dose-Response Relationship, Drug Drug Carriers Electric Impedance Endothelial Cells - drug effects Endothelial Cells - metabolism Female Gadolinium DTPA - metabolism imaging methods Injections, Intravenous Intercellular Junctions - drug effects Intercellular Junctions - metabolism Madin Darby Canine Kidney Cells Magnetic Resonance Imaging Mannitol - metabolism Mice, Inbred BALB C paracellular transport Peptides, Cyclic - administration & dosage Peptides, Cyclic - metabolism Peptides, Cyclic - pharmacology permeability permeation enhancers Polyethylene Glycols - metabolism Rats, Sprague-Dawley Time Factors |
| title | Modulation of Intercellular Junctions by Cyclic-ADT Peptides as a Method to Reversibly Increase Blood–Brain Barrier Permeability |
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