Iontophoretic device delivery for the localized treatment of pancreatic ductal adenocarcinoma
Poor delivery and systemic toxicity of many cytotoxic agents, such as the recent promising combination chemotherapy regimen of folinic acid (leucovorin), fluorouracil, irinotecan, and oxaliplatin (FOLFIRINOX), restrict their full utility in the treatment of pancreatic cancer. Local delivery of chemo...
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| Veröffentlicht in: | Proceedings of the National Academy of Sciences - PNAS 2016-02, Vol.113 (8), p.2200-2205 |
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| creator | Byrne, James D. Jajja, Mohammad R. N. Schorzman, Allison N. Keeler, Amanda W. Luft, J. Christopher Zamboni, William C. DeSimone, Joseph M. Yeh, Jen Jen |
| description | Poor delivery and systemic toxicity of many cytotoxic agents, such as the recent promising combination chemotherapy regimen of folinic acid (leucovorin), fluorouracil, irinotecan, and oxaliplatin (FOLFIRINOX), restrict their full utility in the treatment of pancreatic cancer. Local delivery of chemotherapies has become possible using iontophoretic devices that are implanted directly onto pancreatic tumors. We have fabricated implantable iontophoretic devices and tested the local iontophoretic delivery of FOLFIRINOX for the treatment of pancreatic cancer in an orthotopic patient-derived xenograft model. Iontophoretic delivery of FOLFIRINOX was found to increase tumor exposure by almost an order of magnitude compared with i.v. delivery with substantially lower plasma concentrations. Mice treated for 7 wk with device FOLFIRINOX experienced significantly greater tumor growth inhibition compared with i.v. FOLFIRINOX. A marker of cell proliferation, K
i-67, was stained, showing a significant reduction in tumor cell proliferation. These data capitalize on the unique ability of an implantable iontophoretic device to deliver much higher concentrations of drug to the tumor compared with i.v. delivery. Local iontophoretic delivery of cytotoxic agents should be considered for the treatment of patients with unresectable nonmetastatic disease and for patients with the need for palliation of local symptoms, and may be considered as a neoadjuvant approach to improve resection rates and outcome in patients with localized and locally advanced pancreatic cancer. |
| doi_str_mv | 10.1073/pnas.1600421113 |
| format | Article |
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i-67, was stained, showing a significant reduction in tumor cell proliferation. These data capitalize on the unique ability of an implantable iontophoretic device to deliver much higher concentrations of drug to the tumor compared with i.v. delivery. Local iontophoretic delivery of cytotoxic agents should be considered for the treatment of patients with unresectable nonmetastatic disease and for patients with the need for palliation of local symptoms, and may be considered as a neoadjuvant approach to improve resection rates and outcome in patients with localized and locally advanced pancreatic cancer.</description><identifier>ISSN: 0027-8424</identifier><identifier>EISSN: 1091-6490</identifier><identifier>DOI: 10.1073/pnas.1600421113</identifier><identifier>PMID: 26858448</identifier><language>eng</language><publisher>United States: National Academy of Sciences</publisher><subject><![CDATA[Animals ; Antineoplastic Combined Chemotherapy Protocols - administration & dosage ; Antineoplastic Combined Chemotherapy Protocols - pharmacokinetics ; Biological Sciences ; Camptothecin - administration & dosage ; Camptothecin - analogs & derivatives ; Camptothecin - pharmacokinetics ; Carcinoma, Pancreatic Ductal - drug therapy ; Carcinoma, Pancreatic Ductal - metabolism ; Carcinoma, Pancreatic Ductal - pathology ; Cell Proliferation - drug effects ; Chemotherapy ; Cytotoxicity ; Fluorouracil - administration & dosage ; Fluorouracil - pharmacokinetics ; Humans ; Infusion Pumps, Implantable ; Ions ; Iontophoresis - instrumentation ; Leucovorin - administration & dosage ; Leucovorin - pharmacokinetics ; Mice ; Mice, Nude ; Organoplatinum Compounds - administration & dosage ; Organoplatinum Compounds - pharmacokinetics ; Pancreatic cancer ; Pancreatic Neoplasms - drug therapy ; Pancreatic Neoplasms - metabolism ; Pancreatic Neoplasms - pathology ; Rodents ; Toxicity ; Xenograft Model Antitumor Assays]]></subject><ispartof>Proceedings of the National Academy of Sciences - PNAS, 2016-02, Vol.113 (8), p.2200-2205</ispartof><rights>Volumes 1–89 and 106–113, copyright as a collective work only; author(s) retains copyright to individual articles</rights><rights>Copyright National Academy of Sciences Feb 23, 2016</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c466t-4c7e949730c8fe4fb1b736bad663470c5e4e59eaa69507eec78f457e5cafc4623</citedby><cites>FETCH-LOGICAL-c466t-4c7e949730c8fe4fb1b736bad663470c5e4e59eaa69507eec78f457e5cafc4623</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Uhttp://www.pnas.org/content/113/8.cover.gif</thumbnail><linktopdf>$$Uhttps://www.jstor.org/stable/pdf/26467830$$EPDF$$P50$$Gjstor$$H</linktopdf><linktohtml>$$Uhttps://www.jstor.org/stable/26467830$$EHTML$$P50$$Gjstor$$H</linktohtml><link.rule.ids>230,314,723,776,780,799,881,27901,27902,53766,53768,57992,58225</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26858448$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Byrne, James D.</creatorcontrib><creatorcontrib>Jajja, Mohammad R. N.</creatorcontrib><creatorcontrib>Schorzman, Allison N.</creatorcontrib><creatorcontrib>Keeler, Amanda W.</creatorcontrib><creatorcontrib>Luft, J. Christopher</creatorcontrib><creatorcontrib>Zamboni, William C.</creatorcontrib><creatorcontrib>DeSimone, Joseph M.</creatorcontrib><creatorcontrib>Yeh, Jen Jen</creatorcontrib><title>Iontophoretic device delivery for the localized treatment of pancreatic ductal adenocarcinoma</title><title>Proceedings of the National Academy of Sciences - PNAS</title><addtitle>Proc Natl Acad Sci U S A</addtitle><description>Poor delivery and systemic toxicity of many cytotoxic agents, such as the recent promising combination chemotherapy regimen of folinic acid (leucovorin), fluorouracil, irinotecan, and oxaliplatin (FOLFIRINOX), restrict their full utility in the treatment of pancreatic cancer. Local delivery of chemotherapies has become possible using iontophoretic devices that are implanted directly onto pancreatic tumors. We have fabricated implantable iontophoretic devices and tested the local iontophoretic delivery of FOLFIRINOX for the treatment of pancreatic cancer in an orthotopic patient-derived xenograft model. Iontophoretic delivery of FOLFIRINOX was found to increase tumor exposure by almost an order of magnitude compared with i.v. delivery with substantially lower plasma concentrations. Mice treated for 7 wk with device FOLFIRINOX experienced significantly greater tumor growth inhibition compared with i.v. FOLFIRINOX. A marker of cell proliferation, K
i-67, was stained, showing a significant reduction in tumor cell proliferation. These data capitalize on the unique ability of an implantable iontophoretic device to deliver much higher concentrations of drug to the tumor compared with i.v. delivery. Local iontophoretic delivery of cytotoxic agents should be considered for the treatment of patients with unresectable nonmetastatic disease and for patients with the need for palliation of local symptoms, and may be considered as a neoadjuvant approach to improve resection rates and outcome in patients with localized and locally advanced pancreatic cancer.</description><subject>Animals</subject><subject>Antineoplastic Combined Chemotherapy Protocols - administration & dosage</subject><subject>Antineoplastic Combined Chemotherapy Protocols - pharmacokinetics</subject><subject>Biological Sciences</subject><subject>Camptothecin - administration & dosage</subject><subject>Camptothecin - analogs & derivatives</subject><subject>Camptothecin - pharmacokinetics</subject><subject>Carcinoma, Pancreatic Ductal - drug therapy</subject><subject>Carcinoma, Pancreatic Ductal - metabolism</subject><subject>Carcinoma, Pancreatic Ductal - pathology</subject><subject>Cell Proliferation - drug effects</subject><subject>Chemotherapy</subject><subject>Cytotoxicity</subject><subject>Fluorouracil - administration & dosage</subject><subject>Fluorouracil - pharmacokinetics</subject><subject>Humans</subject><subject>Infusion Pumps, Implantable</subject><subject>Ions</subject><subject>Iontophoresis - instrumentation</subject><subject>Leucovorin - administration & dosage</subject><subject>Leucovorin - pharmacokinetics</subject><subject>Mice</subject><subject>Mice, Nude</subject><subject>Organoplatinum Compounds - administration & dosage</subject><subject>Organoplatinum Compounds - pharmacokinetics</subject><subject>Pancreatic cancer</subject><subject>Pancreatic Neoplasms - drug therapy</subject><subject>Pancreatic Neoplasms - metabolism</subject><subject>Pancreatic Neoplasms - pathology</subject><subject>Rodents</subject><subject>Toxicity</subject><subject>Xenograft Model Antitumor Assays</subject><issn>0027-8424</issn><issn>1091-6490</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpdkc-L1DAUx4Mo7rh69qQUvHjp7kuTJulFkMUfCwte9Cghk746GdqkJunA-tebMus4enqEfL4f3uNLyEsKVxQku569SVdUAPCGUsoekQ2FjtaCd_CYbAAaWSve8AvyLKU9AHStgqfkohGqVZyrDfl-G3wO8y5EzM5WPR6cxTJGd8B4Xw0hVnmH1RisGd0v7Ksc0eQJfa7CUM3G2_W9JhebzViZHn1ho3U-TOY5eTKYMeGLh3lJvn388PXmc3335dPtzfu72nIhcs2txI53koFVA_JhS7eSia3phWBcgm2RY9uhMaJrQSJaqQbeSmytGYqhYZfk3dE7L9sJe1vWi2bUc3STifc6GKf__fFup3-Eg-ZSCt7yInj7IIjh54Ip68kli-NoPIYlaSqFokJQtqJv_kP3YYm-nFco2fCWld0LdX2kbAwpRRxOy1DQa3V6rU7_ra4kXp_fcOL_dHUGrMmTjjKtdNMAFODVEdinHOKZgAupGLDf0TKq6w</recordid><startdate>20160223</startdate><enddate>20160223</enddate><creator>Byrne, James D.</creator><creator>Jajja, Mohammad R. 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N.</au><au>Schorzman, Allison N.</au><au>Keeler, Amanda W.</au><au>Luft, J. Christopher</au><au>Zamboni, William C.</au><au>DeSimone, Joseph M.</au><au>Yeh, Jen Jen</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Iontophoretic device delivery for the localized treatment of pancreatic ductal adenocarcinoma</atitle><jtitle>Proceedings of the National Academy of Sciences - PNAS</jtitle><addtitle>Proc Natl Acad Sci U S A</addtitle><date>2016-02-23</date><risdate>2016</risdate><volume>113</volume><issue>8</issue><spage>2200</spage><epage>2205</epage><pages>2200-2205</pages><issn>0027-8424</issn><eissn>1091-6490</eissn><abstract>Poor delivery and systemic toxicity of many cytotoxic agents, such as the recent promising combination chemotherapy regimen of folinic acid (leucovorin), fluorouracil, irinotecan, and oxaliplatin (FOLFIRINOX), restrict their full utility in the treatment of pancreatic cancer. Local delivery of chemotherapies has become possible using iontophoretic devices that are implanted directly onto pancreatic tumors. We have fabricated implantable iontophoretic devices and tested the local iontophoretic delivery of FOLFIRINOX for the treatment of pancreatic cancer in an orthotopic patient-derived xenograft model. Iontophoretic delivery of FOLFIRINOX was found to increase tumor exposure by almost an order of magnitude compared with i.v. delivery with substantially lower plasma concentrations. Mice treated for 7 wk with device FOLFIRINOX experienced significantly greater tumor growth inhibition compared with i.v. FOLFIRINOX. A marker of cell proliferation, K
i-67, was stained, showing a significant reduction in tumor cell proliferation. These data capitalize on the unique ability of an implantable iontophoretic device to deliver much higher concentrations of drug to the tumor compared with i.v. delivery. Local iontophoretic delivery of cytotoxic agents should be considered for the treatment of patients with unresectable nonmetastatic disease and for patients with the need for palliation of local symptoms, and may be considered as a neoadjuvant approach to improve resection rates and outcome in patients with localized and locally advanced pancreatic cancer.</abstract><cop>United States</cop><pub>National Academy of Sciences</pub><pmid>26858448</pmid><doi>10.1073/pnas.1600421113</doi><tpages>6</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Animals Antineoplastic Combined Chemotherapy Protocols - administration & dosage Antineoplastic Combined Chemotherapy Protocols - pharmacokinetics Biological Sciences Camptothecin - administration & dosage Camptothecin - analogs & derivatives Camptothecin - pharmacokinetics Carcinoma, Pancreatic Ductal - drug therapy Carcinoma, Pancreatic Ductal - metabolism Carcinoma, Pancreatic Ductal - pathology Cell Proliferation - drug effects Chemotherapy Cytotoxicity Fluorouracil - administration & dosage Fluorouracil - pharmacokinetics Humans Infusion Pumps, Implantable Ions Iontophoresis - instrumentation Leucovorin - administration & dosage Leucovorin - pharmacokinetics Mice Mice, Nude Organoplatinum Compounds - administration & dosage Organoplatinum Compounds - pharmacokinetics Pancreatic cancer Pancreatic Neoplasms - drug therapy Pancreatic Neoplasms - metabolism Pancreatic Neoplasms - pathology Rodents Toxicity Xenograft Model Antitumor Assays |
| title | Iontophoretic device delivery for the localized treatment of pancreatic ductal adenocarcinoma |
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