The Effect of Metal-Chelating Polymers (MCPs) for IIIIn Complexed via the Streptavidin-Biotin System to Trastuzumab Fab Fragments on Tumor and Normal Tissue Distribution in Mice
Identifieur interne : 000368 ( Main/Repository ); précédent : 000367; suivant : 000369The Effect of Metal-Chelating Polymers (MCPs) for IIIIn Complexed via the Streptavidin-Biotin System to Trastuzumab Fab Fragments on Tumor and Normal Tissue Distribution in Mice
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Abstract
Purpose To study the effects of backbone composition and charge of biotin-functionalized metal-chelating polymers (Bi-MCPs) for IIIIn complexed to streptavidin (SAv)-trastuzumab Fab fragments on tumor and normal tissue localization. Methods Bi-MCPs were synthesized with a polyacrylamide [Bi-PAm(DTPA)40], polyaspartamide [Bi-PAsp(DTPA)33] or polyglutamide [Bi-PGlu(DTPA)28] backbone and harboured diethylenetriaminepentaacetic acid (DTPA) chelators for IIIIn. Bi-PAm(DTPA)40 had a net negative charge; Bi-PAsp(DTPA)33 and Bi-PGlu(DTPA)28 were zwitterionic with a net neutral charge. Binding to HER2+ SKOV-3 human ovarian carcinoma cells was determined. Tissue uptake was studied in Balb/c mice by MicroSPECT/CT imaging and biodistribution studies. Tumor and normal tissue uptake of IIIIn-labeled Bi-PAsp(DTPA)33 or Bi-PGlu(DTPA)28 complexed to SAv-Fab was evaluated 48 h post-injection in athymic mice with subcutaneous SKOV-3 xenografts. Results SAv-Fab complexed to MCPs bound specifically to SKOV-3 cells; but specific binding was decreased 2-fold. Liver uptake was 5-13 fold higher for Bi-PAm(DTPA)4o than Bi-PAsp (DTPA)33 and Bi-PGlu(DTPA)28 but was reduced by decreasing negative charges by saturation with indium. IIIIn-Bi-PAsp(DTPA)33 complexed to SAv-Fab accumulated in SKOV-3 tumors; low tumor uptake was found for IIIIn-Bi-PGlu(DTPA)28-SAv-Fab. Conclusions Zwitterionic MCPs composed of polyaspartamide with a net neutral charge are most desirable for constructing radioimmunoconjugates.
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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en" level="a">The Effect of Metal-Chelating Polymers (MCPs) for <sup>III</sup>In Complexed via the Streptavidin-Biotin System to Trastuzumab Fab Fragments on Tumor and Normal Tissue Distribution in Mice</title><author><name sortKey="Boyle, Amanda J" uniqKey="Boyle A">Amanda J. Boyle</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Department of Pharmaceutical Sciences, University of Toronto</s1><s2>Toronto, Ontario M5S 3M2</s2><s3>CAN</s3><sZ>1 aut.</sZ><sZ>5 aut.</sZ><sZ>6 aut.</sZ><sZ>8 aut.</sZ></inist:fA14><country>Canada</country><wicri:noRegion>Toronto, Ontario M5S 3M2</wicri:noRegion></affiliation></author><author><name>PENG LIU</name><affiliation wicri:level="1"><inist:fA14 i1="02"><s1>Department of Chemistry, University of Toronto 80 St. George St.</s1><s2>Toronto, Ontario M5S 3H6</s2><s3>CAN</s3><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>7 aut.</sZ></inist:fA14><country>Canada</country><wicri:noRegion>Toronto, Ontario M5S 3H6</wicri:noRegion></affiliation></author><author><name>YIJIE LU</name><affiliation wicri:level="1"><inist:fA14 i1="02"><s1>Department of Chemistry, University of Toronto 80 St. George St.</s1><s2>Toronto, Ontario M5S 3H6</s2><s3>CAN</s3><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>7 aut.</sZ></inist:fA14><country>Canada</country><wicri:noRegion>Toronto, Ontario M5S 3H6</wicri:noRegion></affiliation></author><author><name sortKey="Weinrich, Dirk" uniqKey="Weinrich D">Dirk Weinrich</name><affiliation wicri:level="1"><inist:fA14 i1="02"><s1>Department of Chemistry, University of Toronto 80 St. George St.</s1><s2>Toronto, Ontario M5S 3H6</s2><s3>CAN</s3><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>7 aut.</sZ></inist:fA14><country>Canada</country><wicri:noRegion>Toronto, Ontario M5S 3H6</wicri:noRegion></affiliation></author><author><name sortKey="Scollard, Deborah A" uniqKey="Scollard D">Deborah A. Scollard</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Department of Pharmaceutical Sciences, University of Toronto</s1><s2>Toronto, Ontario M5S 3M2</s2><s3>CAN</s3><sZ>1 aut.</sZ><sZ>5 aut.</sZ><sZ>6 aut.</sZ><sZ>8 aut.</sZ></inist:fA14><country>Canada</country><wicri:noRegion>Toronto, Ontario M5S 3M2</wicri:noRegion></affiliation></author><author><name sortKey="Njock Mbong, Ghislaine Ngo" uniqKey="Njock Mbong G">Ghislaine Ngo Njock Mbong</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Department of Pharmaceutical Sciences, University of Toronto</s1><s2>Toronto, Ontario M5S 3M2</s2><s3>CAN</s3><sZ>1 aut.</sZ><sZ>5 aut.</sZ><sZ>6 aut.</sZ><sZ>8 aut.</sZ></inist:fA14><country>Canada</country><wicri:noRegion>Toronto, Ontario M5S 3M2</wicri:noRegion></affiliation></author><author><name sortKey="Winnik, Mitchell A" uniqKey="Winnik M">Mitchell A. Winnik</name><affiliation wicri:level="1"><inist:fA14 i1="02"><s1>Department of Chemistry, University of Toronto 80 St. George St.</s1><s2>Toronto, Ontario M5S 3H6</s2><s3>CAN</s3><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>7 aut.</sZ></inist:fA14><country>Canada</country><wicri:noRegion>Toronto, Ontario M5S 3H6</wicri:noRegion></affiliation></author><author><name sortKey="Reilly, Raymond M" uniqKey="Reilly R">Raymond M. Reilly</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Department of Pharmaceutical Sciences, University of Toronto</s1><s2>Toronto, Ontario M5S 3M2</s2><s3>CAN</s3><sZ>1 aut.</sZ><sZ>5 aut.</sZ><sZ>6 aut.</sZ><sZ>8 aut.</sZ></inist:fA14><country>Canada</country><wicri:noRegion>Toronto, Ontario M5S 3M2</wicri:noRegion></affiliation><affiliation wicri:level="1"><inist:fA14 i1="03"><s1>Toronto General Research Institute, University Health Network</s1><s2>Toronto, Ontario M5G 2C4</s2><s3>CAN</s3><sZ>8 aut.</sZ></inist:fA14><country>Canada</country><wicri:noRegion>Toronto, Ontario M5G 2C4</wicri:noRegion></affiliation><affiliation wicri:level="1"><inist:fA14 i1="04"><s1>Department of Medical Imaging, University of Toronto 150 College St.</s1><s2>Toronto, Ontario M5S 3E2</s2><s3>CAN</s3><sZ>8 aut.</sZ></inist:fA14><country>Canada</country><wicri:noRegion>Toronto, Ontario M5S 3E2</wicri:noRegion></affiliation></author></titleStmt><publicationStmt><idno type="inist">13-0113470</idno><date when="2013">2013</date><idno type="stanalyst">PASCAL 13-0113470 INIST</idno><idno type="RBID">Pascal:13-0113470</idno><idno type="wicri:Area/Main/Corpus">001154</idno><idno type="wicri:Area/Main/Repository">000368</idno></publicationStmt><seriesStmt><idno type="ISSN">0724-8741</idno><title level="j" type="abbreviated">Pharm. res.</title><title level="j" type="main">Pharmaceutical research</title></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Animal</term><term>Antineoplastic agent</term><term>Biotin</term><term>Distribution</term><term>Fab-Fragment</term><term>Human Epidermal growth factor Receptor 2</term><term>Immunomodulator</term><term>Malignant tumor</term><term>Metal</term><term>Mouse</term><term>Normal</term><term>Pharmaceutical technology</term><term>Polymer</term><term>Streptavidin</term><term>Tissue</term><term>Trastuzumab</term></keywords><keywords scheme="Pascal" xml:lang="fr"><term>Métal</term><term>Polymère</term><term>Streptavidine</term><term>Biotine</term><term>Trastuzumab</term><term>Fragment peptidique Fab</term><term>Tumeur maligne</term><term>Normal</term><term>Tissu</term><term>Distribution</term><term>Animal</term><term>Souris</term><term>Technologie pharmaceutique</term><term>Anticancéreux</term><term>Immunomodulateur</term><term>Récepteur HER2</term></keywords><keywords scheme="Wicri" type="concept" xml:lang="fr"><term>Métal</term><term>Polymère</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Purpose To study the effects of backbone composition and charge of biotin-functionalized metal-chelating polymers (Bi-MCPs) for <sup>III</sup>In complexed to streptavidin (SAv)-trastuzumab Fab fragments on tumor and normal tissue localization. Methods Bi-MCPs were synthesized with a polyacrylamide [Bi-PAm(DTPA)<sub>40</sub>], polyaspartamide [Bi-PAsp(DTPA)<sub>33</sub>] or polyglutamide [Bi-PGlu(DTPA)<sub>28</sub>] backbone and harboured diethylenetriaminepentaacetic acid (DTPA) chelators for <sup>III</sup>In. Bi-PAm(DTPA)<sub>40 </sub> had a net negative charge; Bi-PAsp(DTPA)<sub>33</sub> and Bi-PGlu(DTPA)<sub>28</sub> were zwitterionic with a net neutral charge. Binding to HER2+ SKOV-3 human ovarian carcinoma cells was determined. Tissue uptake was studied in Balb/c mice by MicroSPECT/CT imaging and biodistribution studies. Tumor and normal tissue uptake of <sup>III</sup>In-labeled Bi-PAsp(DTPA)<sub>33</sub> or Bi-PGlu(DTPA)<sub>28</sub> complexed to SAv-Fab was evaluated 48 h post-injection in athymic mice with subcutaneous SKOV-3 xenografts. Results SAv-Fab complexed to MCPs bound specifically to SKOV-3 cells; but specific binding was decreased 2-fold. Liver uptake was 5-13 fold higher for Bi-PAm(DTPA)<sub>4o</sub> than Bi-PAsp (DTPA)<sub>33</sub> and Bi-PGlu(DTPA)<sub>28</sub> but was reduced by decreasing negative charges by saturation with indium. <sup>III</sup>In-Bi-PAsp(DTPA)<sub>33 </sub> complexed to SAv-Fab accumulated in SKOV-3 tumors; low tumor uptake was found for <sup>III</sup>In-Bi-PGlu(DTPA)<sub>28</sub>-SAv-Fab. Conclusions Zwitterionic MCPs composed of polyaspartamide with a net neutral charge are most desirable for constructing radioimmunoconjugates.</div></front></TEI><inist><standard h6="B"><pA><fA01 i1="01" i2="1"><s0>0724-8741</s0></fA01><fA02 i1="01"><s0>PHREEB</s0></fA02><fA03 i2="1"><s0>Pharm. res.</s0></fA03><fA05><s2>30</s2></fA05><fA06><s2>1</s2></fA06><fA08 i1="01" i2="1" l="ENG"><s1>The Effect of Metal-Chelating Polymers (MCPs) for <sup>III</sup>In Complexed via the Streptavidin-Biotin System to Trastuzumab Fab Fragments on Tumor and Normal Tissue Distribution in Mice</s1></fA08><fA11 i1="01" i2="1"><s1>BOYLE (Amanda J.)</s1></fA11><fA11 i1="02" i2="1"><s1>PENG LIU</s1></fA11><fA11 i1="03" i2="1"><s1>YIJIE LU</s1></fA11><fA11 i1="04" i2="1"><s1>WEINRICH (Dirk)</s1></fA11><fA11 i1="05" i2="1"><s1>SCOLLARD (Deborah A.)</s1></fA11><fA11 i1="06" i2="1"><s1>NJOCK MBONG (Ghislaine Ngo)</s1></fA11><fA11 i1="07" i2="1"><s1>WINNIK (Mitchell A.)</s1></fA11><fA11 i1="08" i2="1"><s1>REILLY (Raymond M.)</s1></fA11><fA14 i1="01"><s1>Department of Pharmaceutical Sciences, University of Toronto</s1><s2>Toronto, Ontario M5S 3M2</s2><s3>CAN</s3><sZ>1 aut.</sZ><sZ>5 aut.</sZ><sZ>6 aut.</sZ><sZ>8 aut.</sZ></fA14><fA14 i1="02"><s1>Department of Chemistry, University of Toronto 80 St. George St.</s1><s2>Toronto, Ontario M5S 3H6</s2><s3>CAN</s3><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>7 aut.</sZ></fA14><fA14 i1="03"><s1>Toronto General Research Institute, University Health Network</s1><s2>Toronto, Ontario M5G 2C4</s2><s3>CAN</s3><sZ>8 aut.</sZ></fA14><fA14 i1="04"><s1>Department of Medical Imaging, University of Toronto 150 College St.</s1><s2>Toronto, Ontario M5S 3E2</s2><s3>CAN</s3><sZ>8 aut.</sZ></fA14><fA20><s1>104-116</s1></fA20><fA21><s1>2013</s1></fA21><fA23 i1="01"><s0>ENG</s0></fA23><fA43 i1="01"><s1>INIST</s1><s2>20257</s2><s5>354000506398980100</s5></fA43><fA44><s0>0000</s0><s1>© 2013 INIST-CNRS. All rights reserved.</s1></fA44><fA45><s0>26 ref.</s0></fA45><fA47 i1="01" i2="1"><s0>13-0113470</s0></fA47><fA60><s1>P</s1><s3>PR</s3></fA60><fA61><s0>A</s0></fA61><fA64 i1="01" i2="1"><s0>Pharmaceutical research</s0></fA64><fA66 i1="01"><s0>USA</s0></fA66><fC01 i1="01" l="ENG"><s0>Purpose To study the effects of backbone composition and charge of biotin-functionalized metal-chelating polymers (Bi-MCPs) for <sup>III</sup>In complexed to streptavidin (SAv)-trastuzumab Fab fragments on tumor and normal tissue localization. Methods Bi-MCPs were synthesized with a polyacrylamide [Bi-PAm(DTPA)<sub>40</sub>], polyaspartamide [Bi-PAsp(DTPA)<sub>33</sub>] or polyglutamide [Bi-PGlu(DTPA)<sub>28</sub>] backbone and harboured diethylenetriaminepentaacetic acid (DTPA) chelators for <sup>III</sup>In. Bi-PAm(DTPA)<sub>40 </sub> had a net negative charge; Bi-PAsp(DTPA)<sub>33</sub> and Bi-PGlu(DTPA)<sub>28</sub> were zwitterionic with a net neutral charge. Binding to HER2+ SKOV-3 human ovarian carcinoma cells was determined. Tissue uptake was studied in Balb/c mice by MicroSPECT/CT imaging and biodistribution studies. Tumor and normal tissue uptake of <sup>III</sup>In-labeled Bi-PAsp(DTPA)<sub>33</sub> or Bi-PGlu(DTPA)<sub>28</sub> complexed to SAv-Fab was evaluated 48 h post-injection in athymic mice with subcutaneous SKOV-3 xenografts. Results SAv-Fab complexed to MCPs bound specifically to SKOV-3 cells; but specific binding was decreased 2-fold. Liver uptake was 5-13 fold higher for Bi-PAm(DTPA)<sub>4o</sub> than Bi-PAsp (DTPA)<sub>33</sub> and Bi-PGlu(DTPA)<sub>28</sub> but was reduced by decreasing negative charges by saturation with indium. <sup>III</sup>In-Bi-PAsp(DTPA)<sub>33 </sub> complexed to SAv-Fab accumulated in SKOV-3 tumors; low tumor uptake was found for <sup>III</sup>In-Bi-PGlu(DTPA)<sub>28</sub>-SAv-Fab. Conclusions Zwitterionic MCPs composed of polyaspartamide with a net neutral charge are most desirable for constructing radioimmunoconjugates.</s0></fC01><fC02 i1="01" i2="X"><s0>002B02A03</s0></fC02><fC03 i1="01" i2="X" l="FRE"><s0>Métal</s0><s2>NC</s2><s5>01</s5></fC03><fC03 i1="01" i2="X" l="ENG"><s0>Metal</s0><s2>NC</s2><s5>01</s5></fC03><fC03 i1="01" i2="X" l="SPA"><s0>Metal</s0><s2>NC</s2><s5>01</s5></fC03><fC03 i1="02" i2="X" l="FRE"><s0>Polymère</s0><s5>02</s5></fC03><fC03 i1="02" i2="X" l="ENG"><s0>Polymer</s0><s5>02</s5></fC03><fC03 i1="02" i2="X" l="SPA"><s0>Polímero</s0><s5>02</s5></fC03><fC03 i1="03" i2="X" l="FRE"><s0>Streptavidine</s0><s5>03</s5></fC03><fC03 i1="03" i2="X" l="ENG"><s0>Streptavidin</s0><s5>03</s5></fC03><fC03 i1="03" i2="X" l="SPA"><s0>Streptavidina</s0><s5>03</s5></fC03><fC03 i1="04" i2="X" l="FRE"><s0>Biotine</s0><s2>FR</s2><s5>04</s5></fC03><fC03 i1="04" i2="X" l="ENG"><s0>Biotin</s0><s2>FR</s2><s5>04</s5></fC03><fC03 i1="04" i2="X" l="SPA"><s0>Biotina</s0><s2>FR</s2><s5>04</s5></fC03><fC03 i1="05" i2="X" l="FRE"><s0>Trastuzumab</s0><s2>NK</s2><s2>FR</s2><s5>05</s5></fC03><fC03 i1="05" i2="X" l="ENG"><s0>Trastuzumab</s0><s2>NK</s2><s2>FR</s2><s5>05</s5></fC03><fC03 i1="05" i2="X" l="SPA"><s0>Trastuzumab</s0><s2>NK</s2><s2>FR</s2><s5>05</s5></fC03><fC03 i1="06" i2="X" l="FRE"><s0>Fragment peptidique Fab</s0><s5>06</s5></fC03><fC03 i1="06" i2="X" l="ENG"><s0>Fab-Fragment</s0><s5>06</s5></fC03><fC03 i1="06" i2="X" l="SPA"><s0>Fragmento peptídico Fab</s0><s5>06</s5></fC03><fC03 i1="07" i2="X" l="FRE"><s0>Tumeur maligne</s0><s2>NM</s2><s5>07</s5></fC03><fC03 i1="07" i2="X" l="ENG"><s0>Malignant tumor</s0><s2>NM</s2><s5>07</s5></fC03><fC03 i1="07" i2="X" l="SPA"><s0>Tumor maligno</s0><s2>NM</s2><s5>07</s5></fC03><fC03 i1="08" i2="X" l="FRE"><s0>Normal</s0><s5>08</s5></fC03><fC03 i1="08" i2="X" l="ENG"><s0>Normal</s0><s5>08</s5></fC03><fC03 i1="08" i2="X" l="SPA"><s0>Normal</s0><s5>08</s5></fC03><fC03 i1="09" i2="X" 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|clé= Pascal:13-0113470
|texte= The Effect of Metal-Chelating Polymers (MCPs) for IIIIn Complexed via the Streptavidin-Biotin System to Trastuzumab Fab Fragments on Tumor and Normal Tissue Distribution in Mice
}}
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