Pulmonary Administration of PEGylated Polylysine Dendrimers: Absorption from the Lung versus Retention within the Lung Is Highly Size-Dependent
The systemic delivery of drugs via the inhaled route is an attractive, needle-free means of improving the systemic exposure of molecules such as peptides and proteins that are poorly absorbed after oral administration. Directed delivery into the lungs also provides a means of increasing drug concent...
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| Veröffentlicht in: | Molecular pharmaceutics 2013-08, Vol.10 (8), p.2986-2995 |
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| creator | Ryan, Gemma M Kaminskas, Lisa M Kelly, Brian D Owen, David J McIntosh, Michelle P Porter, Christopher J. H |
| description | The systemic delivery of drugs via the inhaled route is an attractive, needle-free means of improving the systemic exposure of molecules such as peptides and proteins that are poorly absorbed after oral administration. Directed delivery into the lungs also provides a means of increasing drug concentrations at the site of action for lung-specific disease states such as pulmonary infections and lung cancer. The current study has examined the potential utility of PEGylated polylysine dendrimers as pulmonary delivery agents and in particular sought to explore the relationship between dendrimer size and absorption of the intact construct (as a potential systemic delivery mechanism) versus retention within the lungs (as a potential pulmonary depot for controlled local release). Dendrimer absorption from the lungs was inversely correlated with molecular weight, with approximately 20–30% of the dose of relatively small ( |
| doi_str_mv | 10.1021/mp400091n |
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Dendrimer absorption from the lungs was inversely correlated with molecular weight, with approximately 20–30% of the dose of relatively small (<22 kDa) dendrimers systemically absorbed compared to only 2% absorption for a larger (78 kDa) PEGylated dendrimer. Increasing the molecular weight of the dendrimers led to slower absorption and more prolonged retention in the lung tissue and bronchoalveolar lavage fluid. Oral administration of the two smaller dendrimers confirmed that oral bioavailability of the PEGylated dendrimers was essentially zero and did not contribute to exposure after pulmonary administration. The smaller PEGylated dendrimers were also degraded in the lungs to low molecular weight products that were subsequently absorbed and excreted via the urine, while the larger constructs showed good stability in the lungs. The data suggest first, that small PEGylated dendrimer-based drug delivery systems may be delivered to the blood via inhalation, providing a more attractive alternative to injections, and second that larger PEGylated dendrimers may be retained in the lungs providing the potential for controlled delivery of medications to the blood or lung tissue.</description><identifier>ISSN: 1543-8384</identifier><identifier>EISSN: 1543-8392</identifier><identifier>DOI: 10.1021/mp400091n</identifier><identifier>PMID: 23750747</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Absorption ; Animals ; Dendrimers - administration & dosage ; Dendrimers - chemistry ; Dendrimers - pharmacokinetics ; Lung - metabolism ; Male ; Polyethylene Glycols - chemistry ; Polylysine - chemistry ; Rats ; Rats, Sprague-Dawley</subject><ispartof>Molecular pharmaceutics, 2013-08, Vol.10 (8), p.2986-2995</ispartof><rights>Copyright © 2013 American Chemical Society</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a381t-acd13a0dac635c59f9f2eb3ada13628e8aa366aa4ba915c290c96ab8db00b0883</citedby><cites>FETCH-LOGICAL-a381t-acd13a0dac635c59f9f2eb3ada13628e8aa366aa4ba915c290c96ab8db00b0883</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/mp400091n$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/mp400091n$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,776,780,2752,27053,27901,27902,56713,56763</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23750747$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Ryan, Gemma M</creatorcontrib><creatorcontrib>Kaminskas, Lisa M</creatorcontrib><creatorcontrib>Kelly, Brian D</creatorcontrib><creatorcontrib>Owen, David J</creatorcontrib><creatorcontrib>McIntosh, Michelle P</creatorcontrib><creatorcontrib>Porter, Christopher J. H</creatorcontrib><title>Pulmonary Administration of PEGylated Polylysine Dendrimers: Absorption from the Lung versus Retention within the Lung Is Highly Size-Dependent</title><title>Molecular pharmaceutics</title><addtitle>Mol. Pharmaceutics</addtitle><description>The systemic delivery of drugs via the inhaled route is an attractive, needle-free means of improving the systemic exposure of molecules such as peptides and proteins that are poorly absorbed after oral administration. Directed delivery into the lungs also provides a means of increasing drug concentrations at the site of action for lung-specific disease states such as pulmonary infections and lung cancer. The current study has examined the potential utility of PEGylated polylysine dendrimers as pulmonary delivery agents and in particular sought to explore the relationship between dendrimer size and absorption of the intact construct (as a potential systemic delivery mechanism) versus retention within the lungs (as a potential pulmonary depot for controlled local release). Dendrimer absorption from the lungs was inversely correlated with molecular weight, with approximately 20–30% of the dose of relatively small (<22 kDa) dendrimers systemically absorbed compared to only 2% absorption for a larger (78 kDa) PEGylated dendrimer. Increasing the molecular weight of the dendrimers led to slower absorption and more prolonged retention in the lung tissue and bronchoalveolar lavage fluid. Oral administration of the two smaller dendrimers confirmed that oral bioavailability of the PEGylated dendrimers was essentially zero and did not contribute to exposure after pulmonary administration. The smaller PEGylated dendrimers were also degraded in the lungs to low molecular weight products that were subsequently absorbed and excreted via the urine, while the larger constructs showed good stability in the lungs. The data suggest first, that small PEGylated dendrimer-based drug delivery systems may be delivered to the blood via inhalation, providing a more attractive alternative to injections, and second that larger PEGylated dendrimers may be retained in the lungs providing the potential for controlled delivery of medications to the blood or lung tissue.</description><subject>Absorption</subject><subject>Animals</subject><subject>Dendrimers - administration & dosage</subject><subject>Dendrimers - chemistry</subject><subject>Dendrimers - pharmacokinetics</subject><subject>Lung - metabolism</subject><subject>Male</subject><subject>Polyethylene Glycols - chemistry</subject><subject>Polylysine - chemistry</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><issn>1543-8384</issn><issn>1543-8392</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpt0E1r3DAQBmARWrJpkkP-QNGlkBzcSJbslXtb8rmwkCUfZzO2x7tabMmV7BbnT_QvR8kmm0tPMzAPL8xLyAlnPzmL-XnbScZYxs0eOeCJFJESWfxltys5Id-83zAWyyQW-2QSi2nCpnJ6QP4th6a1BtxIZ1Wrjfa9g15bQ21Nl1c3YwM9VnRpm7EZvTZIL9FUTrfo_C86K7x13RuvnW1pv0a6GMyK_gnnwdN77NG8nf_qfq3NJ5h7eqtX62akD_oZo0vsQmywR-RrDY3H4_d5SJ6urx4vbqPF3c38YraIQCjeR1BWXACroExFUiZZndUxFgIq4CKNFSoAkaYAsoCMJ2WcsTJLoVBVwVjBlBKH5HSb2zn7e0Df5632JTYNGLSDz7nkikuVKBno2ZaWznrvsM678H9oLOcsf-0_3_Uf7Pf32KFosdrJj8ID-LEFUPp8Ywdnwpf_CXoBijGPeA</recordid><startdate>20130805</startdate><enddate>20130805</enddate><creator>Ryan, Gemma M</creator><creator>Kaminskas, Lisa M</creator><creator>Kelly, Brian D</creator><creator>Owen, David J</creator><creator>McIntosh, Michelle P</creator><creator>Porter, Christopher J. 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H</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a381t-acd13a0dac635c59f9f2eb3ada13628e8aa366aa4ba915c290c96ab8db00b0883</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>Absorption</topic><topic>Animals</topic><topic>Dendrimers - administration & dosage</topic><topic>Dendrimers - chemistry</topic><topic>Dendrimers - pharmacokinetics</topic><topic>Lung - metabolism</topic><topic>Male</topic><topic>Polyethylene Glycols - chemistry</topic><topic>Polylysine - chemistry</topic><topic>Rats</topic><topic>Rats, Sprague-Dawley</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Ryan, Gemma M</creatorcontrib><creatorcontrib>Kaminskas, Lisa M</creatorcontrib><creatorcontrib>Kelly, Brian D</creatorcontrib><creatorcontrib>Owen, David J</creatorcontrib><creatorcontrib>McIntosh, Michelle P</creatorcontrib><creatorcontrib>Porter, Christopher J. 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Pharmaceutics</addtitle><date>2013-08-05</date><risdate>2013</risdate><volume>10</volume><issue>8</issue><spage>2986</spage><epage>2995</epage><pages>2986-2995</pages><issn>1543-8384</issn><eissn>1543-8392</eissn><abstract>The systemic delivery of drugs via the inhaled route is an attractive, needle-free means of improving the systemic exposure of molecules such as peptides and proteins that are poorly absorbed after oral administration. Directed delivery into the lungs also provides a means of increasing drug concentrations at the site of action for lung-specific disease states such as pulmonary infections and lung cancer. The current study has examined the potential utility of PEGylated polylysine dendrimers as pulmonary delivery agents and in particular sought to explore the relationship between dendrimer size and absorption of the intact construct (as a potential systemic delivery mechanism) versus retention within the lungs (as a potential pulmonary depot for controlled local release). Dendrimer absorption from the lungs was inversely correlated with molecular weight, with approximately 20–30% of the dose of relatively small (<22 kDa) dendrimers systemically absorbed compared to only 2% absorption for a larger (78 kDa) PEGylated dendrimer. Increasing the molecular weight of the dendrimers led to slower absorption and more prolonged retention in the lung tissue and bronchoalveolar lavage fluid. Oral administration of the two smaller dendrimers confirmed that oral bioavailability of the PEGylated dendrimers was essentially zero and did not contribute to exposure after pulmonary administration. The smaller PEGylated dendrimers were also degraded in the lungs to low molecular weight products that were subsequently absorbed and excreted via the urine, while the larger constructs showed good stability in the lungs. The data suggest first, that small PEGylated dendrimer-based drug delivery systems may be delivered to the blood via inhalation, providing a more attractive alternative to injections, and second that larger PEGylated dendrimers may be retained in the lungs providing the potential for controlled delivery of medications to the blood or lung tissue.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>23750747</pmid><doi>10.1021/mp400091n</doi><tpages>10</tpages></addata></record> |
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| subjects | Absorption Animals Dendrimers - administration & dosage Dendrimers - chemistry Dendrimers - pharmacokinetics Lung - metabolism Male Polyethylene Glycols - chemistry Polylysine - chemistry Rats Rats, Sprague-Dawley |
| title | Pulmonary Administration of PEGylated Polylysine Dendrimers: Absorption from the Lung versus Retention within the Lung Is Highly Size-Dependent |
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