Local co-delivery of rhBMP-2 and cathepsin K inhibitor L006235 in poly(d,l-lactide-co-glycolide) nanospheres
Cathepsin K inhibitors (CKIs) are an emerging class of drugs that are potent antagonists of osteoclastic activity. We speculated that they may be beneficial in bone tissue engineering, where a stress shielded environment can lead to rapid resorption of new bone. Most CKIs require frequent dosing, so...
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| Veröffentlicht in: | Journal of biomedical materials research. Part B, Applied biomaterials Applied biomaterials, 2017-01, Vol.105 (1), p.136-144 |
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| creator | Yu, Nicole Y C Fathi, Ali Murphy, Ciara M Mikulec, Kathy Peacock, Lauren Cantrill, Laurence C Dehghani, Fariba Little, David G Schindeler, Aaron |
| description | Cathepsin K inhibitors (CKIs) are an emerging class of drugs that are potent antagonists of osteoclastic activity. We speculated that they may be beneficial in bone tissue engineering, where a stress shielded environment can lead to rapid resorption of new bone. Most CKIs require frequent dosing, so to achieve a sustained release we manufactured polymer nanoparticles encapsulating the CKI L006235 (CKI/nP). CKI/nP and the collagen matrices that were used to deliver them were characterized by electron microscopy and fluorescent confocal microscopy, and data indicated that the particles were evenly distributed throughout the collagen. Elution studies indicated a linear release of the inhibitor from the CKI/nP, with approximately 2% of the drug being released per day. In an in vivo study, mice were implanted with collagen scaffolds containing rhBMP-2 that were loaded with the CKI/nP. Measurement of bone volume (BV) by microCT showed no significant increase with CKI/nP incorporation, and other parameters similarly showed no statistical differences. Cell culture studies confirmed the activity of the drug, even at low concentrations. These data indicate that polymer nanoparticles are an effective method for sustained drug delivery of a CKI, however, this may not be readily translatable to substantively improved bone tissue engineering outcomes. © 2015 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 136-144, 2017. |
| doi_str_mv | 10.1002/jbm.b.33481 |
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We speculated that they may be beneficial in bone tissue engineering, where a stress shielded environment can lead to rapid resorption of new bone. Most CKIs require frequent dosing, so to achieve a sustained release we manufactured polymer nanoparticles encapsulating the CKI L006235 (CKI/nP). CKI/nP and the collagen matrices that were used to deliver them were characterized by electron microscopy and fluorescent confocal microscopy, and data indicated that the particles were evenly distributed throughout the collagen. Elution studies indicated a linear release of the inhibitor from the CKI/nP, with approximately 2% of the drug being released per day. In an in vivo study, mice were implanted with collagen scaffolds containing rhBMP-2 that were loaded with the CKI/nP. Measurement of bone volume (BV) by microCT showed no significant increase with CKI/nP incorporation, and other parameters similarly showed no statistical differences. Cell culture studies confirmed the activity of the drug, even at low concentrations. These data indicate that polymer nanoparticles are an effective method for sustained drug delivery of a CKI, however, this may not be readily translatable to substantively improved bone tissue engineering outcomes. © 2015 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 136-144, 2017.</description><identifier>ISSN: 1552-4973</identifier><identifier>EISSN: 1552-4981</identifier><identifier>DOI: 10.1002/jbm.b.33481</identifier><identifier>PMID: 26435360</identifier><language>eng</language><publisher>United States: Wiley Subscription Services, Inc</publisher><subject>Animals ; Antagonists ; Benzamides - chemistry ; Benzamides - pharmacology ; Biomedical materials ; Bone Morphogenetic Protein 2 - chemistry ; Bone Morphogenetic Protein 2 - pharmacology ; Bone resorption ; Bones ; Cathepsin K ; Cathepsin K - antagonists & inhibitors ; Cell culture ; Collagen ; Computed tomography ; Confocal microscopy ; Controlled release ; Drug delivery ; Drug delivery systems ; Drug Delivery Systems - methods ; Drug development ; Electron microscopy ; Elution ; Fluorescence ; Humans ; In vivo methods and tests ; Inhibitors ; Low concentrations ; Materials research ; Materials science ; Mice ; Microscopy ; Nanoparticles ; Nanospheres ; Nanospheres - chemistry ; Osteoclasts ; Osteoclasts - metabolism ; Polyglactin 910 - chemistry ; Polyglactin 910 - pharmacology ; Polymers ; Recombinant Proteins - chemistry ; Recombinant Proteins - pharmacology ; Surgical implants ; Sustained release ; Thiazoles - chemistry ; Thiazoles - pharmacology ; Tissue engineering</subject><ispartof>Journal of biomedical materials research. 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Part B, Applied biomaterials</title><addtitle>J Biomed Mater Res B Appl Biomater</addtitle><description>Cathepsin K inhibitors (CKIs) are an emerging class of drugs that are potent antagonists of osteoclastic activity. We speculated that they may be beneficial in bone tissue engineering, where a stress shielded environment can lead to rapid resorption of new bone. Most CKIs require frequent dosing, so to achieve a sustained release we manufactured polymer nanoparticles encapsulating the CKI L006235 (CKI/nP). CKI/nP and the collagen matrices that were used to deliver them were characterized by electron microscopy and fluorescent confocal microscopy, and data indicated that the particles were evenly distributed throughout the collagen. Elution studies indicated a linear release of the inhibitor from the CKI/nP, with approximately 2% of the drug being released per day. In an in vivo study, mice were implanted with collagen scaffolds containing rhBMP-2 that were loaded with the CKI/nP. Measurement of bone volume (BV) by microCT showed no significant increase with CKI/nP incorporation, and other parameters similarly showed no statistical differences. Cell culture studies confirmed the activity of the drug, even at low concentrations. These data indicate that polymer nanoparticles are an effective method for sustained drug delivery of a CKI, however, this may not be readily translatable to substantively improved bone tissue engineering outcomes. © 2015 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 136-144, 2017.</description><subject>Animals</subject><subject>Antagonists</subject><subject>Benzamides - chemistry</subject><subject>Benzamides - pharmacology</subject><subject>Biomedical materials</subject><subject>Bone Morphogenetic Protein 2 - chemistry</subject><subject>Bone Morphogenetic Protein 2 - pharmacology</subject><subject>Bone resorption</subject><subject>Bones</subject><subject>Cathepsin K</subject><subject>Cathepsin K - antagonists & inhibitors</subject><subject>Cell culture</subject><subject>Collagen</subject><subject>Computed tomography</subject><subject>Confocal microscopy</subject><subject>Controlled release</subject><subject>Drug delivery</subject><subject>Drug delivery systems</subject><subject>Drug Delivery Systems - methods</subject><subject>Drug development</subject><subject>Electron microscopy</subject><subject>Elution</subject><subject>Fluorescence</subject><subject>Humans</subject><subject>In vivo methods and tests</subject><subject>Inhibitors</subject><subject>Low concentrations</subject><subject>Materials research</subject><subject>Materials science</subject><subject>Mice</subject><subject>Microscopy</subject><subject>Nanoparticles</subject><subject>Nanospheres</subject><subject>Nanospheres - chemistry</subject><subject>Osteoclasts</subject><subject>Osteoclasts - metabolism</subject><subject>Polyglactin 910 - chemistry</subject><subject>Polyglactin 910 - pharmacology</subject><subject>Polymers</subject><subject>Recombinant Proteins - chemistry</subject><subject>Recombinant Proteins - pharmacology</subject><subject>Surgical implants</subject><subject>Sustained release</subject><subject>Thiazoles - chemistry</subject><subject>Thiazoles - pharmacology</subject><subject>Tissue engineering</subject><issn>1552-4973</issn><issn>1552-4981</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kL1PwzAQxS0EouVjYkeWWIpEiu2znWSEii9RBAPMkZ3YJJUbhzhFyn-PJQoDA9PdPf307t0hdELJnBLCLld6PddzAJ7RHTSlQrCE5xnd_e1TmKCDEFYRlkTAPpowyUGAJFPklr5UDpc-qYxrPk0_Ym9xX18_vSQMq7bCpRpq04WmxY-4aetGN4Pv8ZIQyUBEBXfejbPqwiVOlUNTmSSavbux9C4O57hVrQ9dbXoTjtCeVS6Y4209RG-3N6-L-2T5fPewuFomHZPpkKS5kZkBY4lWQHSqtaFal5XMgXCqhU01yUFbwSEHKwVPIeW8slVpCbfx3EM0-_btev-xMWEo1k0ojXOqNX4TCpoxKTljaR7Rsz_oym_6NqYrGABlLI9L_6NoJmJoyDmL1OmW2ui1qYqub9aqH4ufb8MXwd193A</recordid><startdate>201701</startdate><enddate>201701</enddate><creator>Yu, Nicole Y C</creator><creator>Fathi, Ali</creator><creator>Murphy, Ciara M</creator><creator>Mikulec, Kathy</creator><creator>Peacock, Lauren</creator><creator>Cantrill, Laurence C</creator><creator>Dehghani, Fariba</creator><creator>Little, David G</creator><creator>Schindeler, Aaron</creator><general>Wiley Subscription Services, Inc</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>7QF</scope><scope>7QO</scope><scope>7QQ</scope><scope>7SC</scope><scope>7SE</scope><scope>7SP</scope><scope>7SR</scope><scope>7T7</scope><scope>7TA</scope><scope>7TB</scope><scope>7U5</scope><scope>8BQ</scope><scope>8FD</scope><scope>C1K</scope><scope>F28</scope><scope>FR3</scope><scope>H8D</scope><scope>H8G</scope><scope>JG9</scope><scope>JQ2</scope><scope>K9.</scope><scope>KR7</scope><scope>L7M</scope><scope>L~C</scope><scope>L~D</scope><scope>P64</scope><scope>7X8</scope></search><sort><creationdate>201701</creationdate><title>Local co-delivery of rhBMP-2 and cathepsin K inhibitor L006235 in poly(d,l-lactide-co-glycolide) nanospheres</title><author>Yu, Nicole Y C ; 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Part B, Applied biomaterials</jtitle><addtitle>J Biomed Mater Res B Appl Biomater</addtitle><date>2017-01</date><risdate>2017</risdate><volume>105</volume><issue>1</issue><spage>136</spage><epage>144</epage><pages>136-144</pages><issn>1552-4973</issn><eissn>1552-4981</eissn><abstract>Cathepsin K inhibitors (CKIs) are an emerging class of drugs that are potent antagonists of osteoclastic activity. We speculated that they may be beneficial in bone tissue engineering, where a stress shielded environment can lead to rapid resorption of new bone. Most CKIs require frequent dosing, so to achieve a sustained release we manufactured polymer nanoparticles encapsulating the CKI L006235 (CKI/nP). CKI/nP and the collagen matrices that were used to deliver them were characterized by electron microscopy and fluorescent confocal microscopy, and data indicated that the particles were evenly distributed throughout the collagen. Elution studies indicated a linear release of the inhibitor from the CKI/nP, with approximately 2% of the drug being released per day. In an in vivo study, mice were implanted with collagen scaffolds containing rhBMP-2 that were loaded with the CKI/nP. Measurement of bone volume (BV) by microCT showed no significant increase with CKI/nP incorporation, and other parameters similarly showed no statistical differences. Cell culture studies confirmed the activity of the drug, even at low concentrations. These data indicate that polymer nanoparticles are an effective method for sustained drug delivery of a CKI, however, this may not be readily translatable to substantively improved bone tissue engineering outcomes. © 2015 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 136-144, 2017.</abstract><cop>United States</cop><pub>Wiley Subscription Services, Inc</pub><pmid>26435360</pmid><doi>10.1002/jbm.b.33481</doi><tpages>9</tpages></addata></record> |
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| subjects | Animals Antagonists Benzamides - chemistry Benzamides - pharmacology Biomedical materials Bone Morphogenetic Protein 2 - chemistry Bone Morphogenetic Protein 2 - pharmacology Bone resorption Bones Cathepsin K Cathepsin K - antagonists & inhibitors Cell culture Collagen Computed tomography Confocal microscopy Controlled release Drug delivery Drug delivery systems Drug Delivery Systems - methods Drug development Electron microscopy Elution Fluorescence Humans In vivo methods and tests Inhibitors Low concentrations Materials research Materials science Mice Microscopy Nanoparticles Nanospheres Nanospheres - chemistry Osteoclasts Osteoclasts - metabolism Polyglactin 910 - chemistry Polyglactin 910 - pharmacology Polymers Recombinant Proteins - chemistry Recombinant Proteins - pharmacology Surgical implants Sustained release Thiazoles - chemistry Thiazoles - pharmacology Tissue engineering |
| title | Local co-delivery of rhBMP-2 and cathepsin K inhibitor L006235 in poly(d,l-lactide-co-glycolide) nanospheres |
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