Generation-6 hydroxyl PAMAM dendrimers improve CNS penetration from intravenous administration in a large animal brain injury model
Hypothermic circulatory arrest (HCA) provides neuroprotection during cardiac surgery but entails an ischemic period that can lead to excitotoxicity, neuroinflammation, and subsequent neurologic injury. Hydroxyl polyamidoamine (PAMAM) dendrimers target activated microglia and damaged neurons in the i...
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| Veröffentlicht in: | Journal of controlled release 2017-03, Vol.249, p.173-182 |
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| creator | Zhang, Fan Trent Magruder, J. Lin, Yi-An Crawford, Todd C. Grimm, Joshua C. Sciortino, Christopher M. Wilson, Mary Ann Blue, Mary E. Kannan, Sujatha Johnston, Michael V. Baumgartner, William A. Kannan, Rangaramanujam M. |
| description | Hypothermic circulatory arrest (HCA) provides neuroprotection during cardiac surgery but entails an ischemic period that can lead to excitotoxicity, neuroinflammation, and subsequent neurologic injury. Hydroxyl polyamidoamine (PAMAM) dendrimers target activated microglia and damaged neurons in the injured brain, and deliver therapeutics in small and large animal models. We investigated the effect of dendrimer size on brain uptake and explored the pharmacokinetics in a clinically-relevant canine model of HCA-induced brain injury. Generation 6 (G6, ~6.7nm) dendrimers showed extended blood circulation times and increased accumulation in the injured brain compared to generation 4 dendrimers (G4, ~4.3nm), which were undetectable in the brain by 48h after final administration. High levels of G6 dendrimers were found in cerebrospinal fluid (CSF) of injured animals with a CSF/serum ratio of ~20% at peak, a ratio higher than that of many neurologic pharmacotherapies already in clinical use. Brain penetration (measured by drug CSF/serum level) of G6 dendrimers correlated with the severity of neuroinflammation observed. G6 dendrimers also showed decreased renal clearance rate, slightly increased liver and spleen uptake compared to G4 dendrimers. These results, in a large animal model, may offer insights into the potential clinical translation of dendrimers.
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| doi_str_mv | 10.1016/j.jconrel.2017.01.032 |
| format | Article |
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[Display omitted]</description><identifier>ISSN: 0168-3659</identifier><identifier>EISSN: 1873-4995</identifier><identifier>DOI: 10.1016/j.jconrel.2017.01.032</identifier><identifier>PMID: 28137632</identifier><language>eng</language><publisher>Netherlands: Elsevier B.V</publisher><subject>animal models ; Animals ; Biodistribution ; blood circulation ; blood serum ; brain ; Brain - metabolism ; Brain Injuries - drug therapy ; Brain Injuries - metabolism ; Brain penetration ; Canine model ; cerebrospinal fluid ; CSF/serum ratio ; Dendrimer ; Dendrimers - administration & dosage ; Dendrimers - chemistry ; Dendrimers - pharmacokinetics ; Disease Models, Animal ; Dogs ; Drug Carriers - administration & dosage ; Drug Carriers - chemistry ; Drug Carriers - pharmacokinetics ; Drug Delivery Systems ; drugs ; Hypothermic circulatory arrest ; intravenous injection ; Kidney - metabolism ; liver ; Liver - metabolism ; Male ; neuroglia ; neurons ; neuroprotective effect ; pharmacokinetics ; renal clearance ; spleen ; surgery</subject><ispartof>Journal of controlled release, 2017-03, Vol.249, p.173-182</ispartof><rights>2017 Elsevier B.V.</rights><rights>Copyright © 2017 Elsevier B.V. All rights reserved.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c537t-3821f720aeb13306f4c5aec6ad424a6822babc5cd2de2b6c5e46c4a1d8d3bc833</citedby><cites>FETCH-LOGICAL-c537t-3821f720aeb13306f4c5aec6ad424a6822babc5cd2de2b6c5e46c4a1d8d3bc833</cites><orcidid>0000-0002-8806-0600 ; 0000-0001-5598-7285</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0168365916307969$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>230,314,776,780,881,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/28137632$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Zhang, Fan</creatorcontrib><creatorcontrib>Trent Magruder, J.</creatorcontrib><creatorcontrib>Lin, Yi-An</creatorcontrib><creatorcontrib>Crawford, Todd C.</creatorcontrib><creatorcontrib>Grimm, Joshua C.</creatorcontrib><creatorcontrib>Sciortino, Christopher M.</creatorcontrib><creatorcontrib>Wilson, Mary Ann</creatorcontrib><creatorcontrib>Blue, Mary E.</creatorcontrib><creatorcontrib>Kannan, Sujatha</creatorcontrib><creatorcontrib>Johnston, Michael V.</creatorcontrib><creatorcontrib>Baumgartner, William A.</creatorcontrib><creatorcontrib>Kannan, Rangaramanujam M.</creatorcontrib><title>Generation-6 hydroxyl PAMAM dendrimers improve CNS penetration from intravenous administration in a large animal brain injury model</title><title>Journal of controlled release</title><addtitle>J Control Release</addtitle><description>Hypothermic circulatory arrest (HCA) provides neuroprotection during cardiac surgery but entails an ischemic period that can lead to excitotoxicity, neuroinflammation, and subsequent neurologic injury. Hydroxyl polyamidoamine (PAMAM) dendrimers target activated microglia and damaged neurons in the injured brain, and deliver therapeutics in small and large animal models. We investigated the effect of dendrimer size on brain uptake and explored the pharmacokinetics in a clinically-relevant canine model of HCA-induced brain injury. Generation 6 (G6, ~6.7nm) dendrimers showed extended blood circulation times and increased accumulation in the injured brain compared to generation 4 dendrimers (G4, ~4.3nm), which were undetectable in the brain by 48h after final administration. High levels of G6 dendrimers were found in cerebrospinal fluid (CSF) of injured animals with a CSF/serum ratio of ~20% at peak, a ratio higher than that of many neurologic pharmacotherapies already in clinical use. Brain penetration (measured by drug CSF/serum level) of G6 dendrimers correlated with the severity of neuroinflammation observed. G6 dendrimers also showed decreased renal clearance rate, slightly increased liver and spleen uptake compared to G4 dendrimers. These results, in a large animal model, may offer insights into the potential clinical translation of dendrimers.
[Display omitted]</description><subject>animal models</subject><subject>Animals</subject><subject>Biodistribution</subject><subject>blood circulation</subject><subject>blood serum</subject><subject>brain</subject><subject>Brain - metabolism</subject><subject>Brain Injuries - drug therapy</subject><subject>Brain Injuries - metabolism</subject><subject>Brain penetration</subject><subject>Canine model</subject><subject>cerebrospinal fluid</subject><subject>CSF/serum ratio</subject><subject>Dendrimer</subject><subject>Dendrimers - administration & dosage</subject><subject>Dendrimers - chemistry</subject><subject>Dendrimers - pharmacokinetics</subject><subject>Disease Models, Animal</subject><subject>Dogs</subject><subject>Drug Carriers - administration & dosage</subject><subject>Drug Carriers - chemistry</subject><subject>Drug Carriers - pharmacokinetics</subject><subject>Drug Delivery Systems</subject><subject>drugs</subject><subject>Hypothermic circulatory arrest</subject><subject>intravenous injection</subject><subject>Kidney - metabolism</subject><subject>liver</subject><subject>Liver - metabolism</subject><subject>Male</subject><subject>neuroglia</subject><subject>neurons</subject><subject>neuroprotective effect</subject><subject>pharmacokinetics</subject><subject>renal clearance</subject><subject>spleen</subject><subject>surgery</subject><issn>0168-3659</issn><issn>1873-4995</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFUU1vEzEUtBCIhsJPAPnIZbf-Wu_mAoqiUiq1gAScLa_9tvXKawd7E5EzfxxHSSs49WTZb2b8Zgaht5TUlFB5MdajiSGBrxmhbU1oTTh7hha0a3kllsvmOVoUXFdx2SzP0KucR0JIw0X7Ep2xjvJWcrZAf64gQNKzi6GS-H5vU_y99_jb6nZ1iy0Em9wEKWM3bVLcAV5_-Y43hTIfOXhIccIulOsOQtxmrO3kgssPcxewxl6nO8A6uEl73CftDu_jNu3xFC341-jFoH2GN6fzHP38dPlj_bm6-Xp1vV7dVKbh7VzxjtGhZURDTzknchCm0WCktoIJLTvGet2bxlhmgfXSNCCkEZrazvLedJyfow9H3c22n8AaOKzt1aZY1Gmvonbq_0lw9-ou7lTDGeesLQLvTwIp_tpCntXksgHvdYDiXbGSsCCSt-JJKO1K_IxwKgu0OUJNijknGB43okQdulajOnWtDl0rQlXpuvDe_WvnkfVQbgF8PAKghLpzkFQ2DoIB6xKYWdnonvjiL68LwV8</recordid><startdate>20170310</startdate><enddate>20170310</enddate><creator>Zhang, Fan</creator><creator>Trent Magruder, J.</creator><creator>Lin, Yi-An</creator><creator>Crawford, Todd C.</creator><creator>Grimm, Joshua C.</creator><creator>Sciortino, Christopher M.</creator><creator>Wilson, Mary Ann</creator><creator>Blue, Mary E.</creator><creator>Kannan, Sujatha</creator><creator>Johnston, Michael V.</creator><creator>Baumgartner, William A.</creator><creator>Kannan, Rangaramanujam M.</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>7X8</scope><scope>7S9</scope><scope>L.6</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-8806-0600</orcidid><orcidid>https://orcid.org/0000-0001-5598-7285</orcidid></search><sort><creationdate>20170310</creationdate><title>Generation-6 hydroxyl PAMAM dendrimers improve CNS penetration from intravenous administration in a large animal brain injury model</title><author>Zhang, Fan ; Trent Magruder, J. ; Lin, Yi-An ; Crawford, Todd C. ; Grimm, Joshua C. ; Sciortino, Christopher M. ; Wilson, Mary Ann ; Blue, Mary E. ; Kannan, Sujatha ; Johnston, Michael V. ; Baumgartner, William A. ; Kannan, Rangaramanujam M.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c537t-3821f720aeb13306f4c5aec6ad424a6822babc5cd2de2b6c5e46c4a1d8d3bc833</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>animal models</topic><topic>Animals</topic><topic>Biodistribution</topic><topic>blood circulation</topic><topic>blood serum</topic><topic>brain</topic><topic>Brain - metabolism</topic><topic>Brain Injuries - drug therapy</topic><topic>Brain Injuries - metabolism</topic><topic>Brain penetration</topic><topic>Canine model</topic><topic>cerebrospinal fluid</topic><topic>CSF/serum ratio</topic><topic>Dendrimer</topic><topic>Dendrimers - administration & dosage</topic><topic>Dendrimers - chemistry</topic><topic>Dendrimers - pharmacokinetics</topic><topic>Disease Models, Animal</topic><topic>Dogs</topic><topic>Drug Carriers - administration & dosage</topic><topic>Drug Carriers - chemistry</topic><topic>Drug Carriers - pharmacokinetics</topic><topic>Drug Delivery Systems</topic><topic>drugs</topic><topic>Hypothermic circulatory arrest</topic><topic>intravenous injection</topic><topic>Kidney - metabolism</topic><topic>liver</topic><topic>Liver - metabolism</topic><topic>Male</topic><topic>neuroglia</topic><topic>neurons</topic><topic>neuroprotective effect</topic><topic>pharmacokinetics</topic><topic>renal clearance</topic><topic>spleen</topic><topic>surgery</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Zhang, Fan</creatorcontrib><creatorcontrib>Trent Magruder, J.</creatorcontrib><creatorcontrib>Lin, Yi-An</creatorcontrib><creatorcontrib>Crawford, Todd C.</creatorcontrib><creatorcontrib>Grimm, Joshua C.</creatorcontrib><creatorcontrib>Sciortino, Christopher M.</creatorcontrib><creatorcontrib>Wilson, Mary Ann</creatorcontrib><creatorcontrib>Blue, Mary E.</creatorcontrib><creatorcontrib>Kannan, Sujatha</creatorcontrib><creatorcontrib>Johnston, Michael V.</creatorcontrib><creatorcontrib>Baumgartner, William A.</creatorcontrib><creatorcontrib>Kannan, Rangaramanujam M.</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>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>Zhang, Fan</au><au>Trent Magruder, J.</au><au>Lin, Yi-An</au><au>Crawford, Todd C.</au><au>Grimm, Joshua C.</au><au>Sciortino, Christopher M.</au><au>Wilson, Mary Ann</au><au>Blue, Mary E.</au><au>Kannan, Sujatha</au><au>Johnston, Michael V.</au><au>Baumgartner, William A.</au><au>Kannan, Rangaramanujam M.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Generation-6 hydroxyl PAMAM dendrimers improve CNS penetration from intravenous administration in a large animal brain injury model</atitle><jtitle>Journal of controlled release</jtitle><addtitle>J Control Release</addtitle><date>2017-03-10</date><risdate>2017</risdate><volume>249</volume><spage>173</spage><epage>182</epage><pages>173-182</pages><issn>0168-3659</issn><eissn>1873-4995</eissn><abstract>Hypothermic circulatory arrest (HCA) provides neuroprotection during cardiac surgery but entails an ischemic period that can lead to excitotoxicity, neuroinflammation, and subsequent neurologic injury. Hydroxyl polyamidoamine (PAMAM) dendrimers target activated microglia and damaged neurons in the injured brain, and deliver therapeutics in small and large animal models. We investigated the effect of dendrimer size on brain uptake and explored the pharmacokinetics in a clinically-relevant canine model of HCA-induced brain injury. Generation 6 (G6, ~6.7nm) dendrimers showed extended blood circulation times and increased accumulation in the injured brain compared to generation 4 dendrimers (G4, ~4.3nm), which were undetectable in the brain by 48h after final administration. High levels of G6 dendrimers were found in cerebrospinal fluid (CSF) of injured animals with a CSF/serum ratio of ~20% at peak, a ratio higher than that of many neurologic pharmacotherapies already in clinical use. Brain penetration (measured by drug CSF/serum level) of G6 dendrimers correlated with the severity of neuroinflammation observed. G6 dendrimers also showed decreased renal clearance rate, slightly increased liver and spleen uptake compared to G4 dendrimers. These results, in a large animal model, may offer insights into the potential clinical translation of dendrimers.
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| ispartof | Journal of controlled release, 2017-03, Vol.249, p.173-182 |
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| source | MEDLINE; Elsevier ScienceDirect Journals |
| subjects | animal models Animals Biodistribution blood circulation blood serum brain Brain - metabolism Brain Injuries - drug therapy Brain Injuries - metabolism Brain penetration Canine model cerebrospinal fluid CSF/serum ratio Dendrimer Dendrimers - administration & dosage Dendrimers - chemistry Dendrimers - pharmacokinetics Disease Models, Animal Dogs Drug Carriers - administration & dosage Drug Carriers - chemistry Drug Carriers - pharmacokinetics Drug Delivery Systems drugs Hypothermic circulatory arrest intravenous injection Kidney - metabolism liver Liver - metabolism Male neuroglia neurons neuroprotective effect pharmacokinetics renal clearance spleen surgery |
| title | Generation-6 hydroxyl PAMAM dendrimers improve CNS penetration from intravenous administration in a large animal brain injury model |
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