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Novel Functional Poly(2-Oxazoline)S As Potential Carriers for Biomedical Applications

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Novel Functional Poly(2-Oxazoline)S As Potential Carriers for Biomedical Applications Technische Universität München Department Chemie WACKER-Lehrstuhl für Makromolekulare Chemie Novel Functional Poly(2-oxazoline)s as Potential Carriers for Biomedical Applications Robert Luxenhofer Vollständiger Abdruck der von der Fakultät für Chemie der Technischen Universität München zur Erlangung des akademischen Grades eines Doktors der Naturwissenschaften (Dr. rer. nat.) genehmigten Dissertation. Vorsitzender: Univ.-Prof. Dr. Kai-Olaf Hinrichsen Prüfer der Dissertation: 1. Priv.-Doz. Dr. Rainer Jordan 2. Univ.-Prof. Dr. Horst Kessler 3. Univ.-Prof. Dr. Andreas Türler Die Dissertation wurde am 29.05.2007 bei der Technischen Universität München ein- gereicht und durch das Department Chemie am 26.06.2007 angenommen. In Vivo Veritas! Die vorliegende Arbeit wurde am WACKER-Lehrstuhl für Makromolekulare Chemie (zuvor Lehrstuhl für Makromolekulare Stoffe) im Department Chemie der Technischen Universität München in der Zeit von März 2004 bis Mai 2007 unter der Leitung von Herrn PD Dr. Rainer Jordan angefertigt. Insbesondere möchte ich mich bei meinem Mentor und Betreuer PD Dr. Rainer ´Ray´ Jordan sehr herzlich bedanken, dass er mir die Möglichkeit gegeben hat, an diesem Projekt zu arbeiten. Ich glaube das war die interessanteste Doktorarbeit die ich hätte finden können, selbst wenn ich gesucht hätte. Ich war sehr froh über all die Freiheit die ich hatte, wobei man immer vorbeikommen konnte, wenn man ein Problem hatte. Außerdem bin ich dankbar für die Arbeits- und Konferenzaufenthalte in New York, Flic en Flac, Budapest, San Francisco etc., die ich genießen konnte und die große Geduld mit mir. Prof. Dr.-Ing. Oskar Nuyken und Prof. Dr. Bernhard Rieger danke ich für die Auf- nahme bzw. die Möglichkeit meines Verbleibs am Lehrstuhl. Bei Prof. Nuyken möchte ich mich auch für das entgegengebrachte Vertrauen und das Interesse an meiner Ar- beit danken, sowie die Möglichkeit meine Arbeiten an verschiedenen Gelegenheiten zu präsentieren. Frau Dr.-Ing. Heidi Samarian danke ich für die viele Hilfe hinter den Kulissen. Den Leitern und Mitarbeitern der Gruppen unserer Kooperationspartner gilt ebenso mein großer Dank. Ohne diese Zusammenarbeit wäre nur ein Stumpf dieser Arbeit möglich gewesen. Prof. Dr. Horst Kessler, Prof. Dr. Hans-Jürgen Wester und PD Dr. Markus Essler danke ich für Ihr Interesse an der Entwicklung von polymeren Therapeu- tika. Ihren Mitarbeitern Dr. Lopéz-García, Florian Manzenrieder, Florian Opperer, Oliver Demmer, Andreas Frank, Janine Eckardt, Florian Gärtner und Dr. Thorsten Poethko danke ich für die Synthese der Peptide, Unterstützung bei der Analytik oder der Durchführung bzw. Unterstützung bei der Durchführung der Tierversuche. Prof. Dr. R. J. Gillies, Prof. V. J. Hruby und Dr. L. Xu von der Universität von Ari- zona danke ich für die Durchführung der Affinitätsstudien der MTII Konjugate. Dr. Steffen Jungermann, mein Laborkollege über einen großen Teil der Arbeit, gilt mein großer Dank für die angenehme Zeit. Ich denke Du warst ein Hauptgrund neben dem Projekt, warum ich ein Makro wurde, sicher eine der besseren Entscheidungen meines Lebens. Ausserdem danke ich dir für die ganze Hilfe mit den Computern und für die MALDI Messungen, für die Zeit am Kaffeetisch, die Balkonbiers, die WoW Zeit und das ganze andere Zeug. Ausserdem danke ich allen Mitgliedern der alten und neuen Makros. Insbesondere möchte ich dabei Dr. Benjamin Rossbach (gibt einem das Gefühl KEIN Workaholic sein), Dr. Martin Bortenschlager (immer hervorragend enspannt), Dr. Martin Mayer- shofer (immer ein Hilfe), Dr. Doris Kaufmann (einfach immer Spass), Marin Steenack- ers (das peinliche Gesicht :-D ), Julia Müller (ich will an den SEE!) für das hervorra- gende und entspannte Arbeitsklima über die Jahre danken. Nicht weniger angenehm war die Arbeit in jüngerer Zeit mit den neueren Makros, dafür danke ich Timo Ansel- ment, Andi Feigl, Caro Gantner, Udo Schmidt, Uli Will und allen anderen Makros. Dr. Martin Mayershofer, Dr. Jens Krause, Dr. Tobias Zarka, Julia Müller und Mar- tin Schneider danke ich für die GPC Messungen über die Jahre, Herrn Krause sowie Stephan Huber danke ich für die MALDI-TOF Messungen. Desweiteren gilt mein Dank meinem ’medizinischen Beraterstab’, Melanie Bosse, Mar- got Roth und Dr. Joanna Eger, auch wenn es hauptsächlich ’nur’ darum ging meine Fragerei zu ertragen. “Meinen” Diplomanden Christian Taubmann, Alexander Kurek und Timo Anselment danke ich für die gute und fruchtbare Zusammenarbeit. Meinen Knechten Florian Brandhuber, Sabine Scholz, Manuela Bezen, Tobias Förster, Richard Knapp, Martin Schneider, Jens Emmerich, Alexander Bochen, Anja Friedrich und Max Ehrhardt, meinen Azubis Martin Schellerer und Floriane, von den vielen Praktikanten insbesondere Luisa Long, Christian Benda und Wenting Zhang und zuletzt meiner ersten Bachelorette Anita Schulz, danke ich vielmals für die Unter- stützung bei meiner Arbeit. Ich hoffe und glaube, dass wir voneinander gelernt haben. Ich hoffe auch keine Knechte vergessen zu haben. Für das Korrekturlesen von Teilen dieser Arbeit danke ich meinem Bruder Georg, Timo Anselment, Julia Müller, Florian Manzenrieder und Florian Opperer. Ein spezieller Dank geht an die Rettung in letzter Sekunde, Michael Bank. Meinem Vater, meiner Familie Contents Contents I Abbreviations and Symbols V 1 Introduction 1 2 State of Knowledge 3 2.1 Targeted Drug Delivery . 4 2.1.1 Conventional and non-targeted cancer therapy . 4 2.1.2 Targeting strategies . 5 2.1.3 Summary . 17 2.2 Peptide receptor mediated radionuclide therapy . 17 2.2.1 Peptide receptors as targets . 18 2.2.2 Suitable radionuclides and chelators . 30 2.2.3 PRRT . 37 2.2.4 Polyvalency at work . 41 2.2.5 Summary . 47 2.3 Polymer therapeutics . 48 2.3.1 Biocompatibility of polymers . 48 2.3.2 Concepts and recent examples . 49 2.3.3 Polymer therapeutics in nuclear medicine . 55 2.3.4 Summary . 58 2.4 Poly(2-oxazoline)s . 59 2.4.1 2-Oxazolines . 59 2.4.2 Living polymerization of 2-oxazolines . 61 2.4.3 Chemistry on poly(2-oxazoline)s . 64 I 2.4.4 Biocompatibility of poly(2-oxazoline)s . 69 2.4.5 Summary . 70 2.5 Chemoselective coupling reactions . 71 2.5.1 Aldehyde-aminooxy Coupling . 71 2.5.2 Native chemical ligation . 73 2.5.3 Click-chemistry . 74 2.6 Hydrogels . 75 2.6.1 Hydrogels for biomedical applications . 77 2.6.2 Poly(2-oxazoline) based hydrogels . 78 2.7 Summary . 80 3 Aim of this work 83 4 Results and Discussion 87 4.1 Monomers and linkers . 87 4.2 Polymerizations and kinetic investigations . 90 4.2.1 Linear poly(2-oxazoline)s . 90 4.2.2 Star-like poly(2-oxazoline)s . 104 4.2.3 Summary . 110 4.3 Modifications at the polymer terminus . 111 4.3.1 Removal of the Boc protection group . 111 4.3.2 Attachment of the radionuclide chelator . 116 4.4 Modification of polymer side chains . 121 4.4.1 Removal of the dioxolane protection group . 121 4.4.2 Chemoselective coupling reactions on the polymer side chains . 125 4.4.3 Coupling of peptides . 129 4.5 Radiometallation . 146 4.6 In vivo and in vitro studies . 148 4.6.1 Biodistribution of hydrophilic low molar mass poly(2-oxazoline)s 148 4.6.2 Biodistribution of [68Ga]C2 in tumor bearing mice . 155 4.6.3 In vitro evaluation of poly(2-oxazoline)-MTII conjugates . 164 4.7 Poly(2-oxazoline) hydrogels . 167 4.7.1 Azine hydrogels . 167 4.7.2 Imine hydrogels . 170 II 4.7.3 Urethane cross-linked hydrogel . 171 4.7.4 Oxidative cross-linking . 171 4.7.5 Summary . 173 5 Summary 175 6 Zusammenfassung 183 7 Experimental 191 7.1 General . 191 7.1.1 Equipment and utilities . 191 7.1.2 Reagent and solvents . 192 7.2 Methods . 193 7.2.1 Polymerizations, general synthetic procedure 1, GSP1 . 193 7.2.2 Removal of Boc protection group, general synthetic procedure 2, GSP2 . 194 7.2.3 Isothiocyanate coupling, general synthetic procedure 3, GSP3 . 194 7.2.4 Gas chromatographic on-line kinetic measurement . 195 7.3 Initiator synthesis . 195 7.3.1 Propane-1,3-bistriflate, I1 .....................195 7.3.2 1,1,1-Tris(triflatemethyl)ethane, I2 . 196 7.3.3 Pentaerythritoltetrakistriflate, I3 . 197 7.4 Monomer synthesis . 198 7.4.1 2-(Pent-4-ynyl)-2-oxazoline . 198 7.4.2 2-(4-Ethynlyphenyl)-2-oxazoline . 200 7.5 Linker for native chemical ligation . 203 7.5.1 Methyl 2-azidoacetate . 203 7.5.2 Ethyl (2-azido)thioacetate . 204 7.5.3 Ethyl (2-bromo)thioacetate . 205 7.5.4 tert-Butyl hydroxycarbamate . 206 7.5.5 Methyl (2-(N-tert-butyloxycarbonyl)aminooxy)acetate . 206 7.6 Polymerizations . 207 7.6.1 Linear homo- and copolymers . 207 7.6.2 Star-like homo- and copolymers . 218 7.7 Polymer analog modifications . 220 III 7.7.1 Boc-deprotection . 220 7.7.2 Click-chemistry . 223 7.7.3 Chelator coupling . 226 7.7.4 Aldehyde deprotection . 233 7.8 Peptide coupling . 236 7.8.1 Click Chemistry . 236 7.8.2 Oxim Ligation . 237 7.8.3 Native Ligation . 242 68 Oxim 7.9 Ga labeling of P(MeOx45 RGD5)PipDOTA . 244 7.10 Preparation of hydrogels . 245 7.10.1 Azine Hydrogels . 245 7.10.2 Imine Hydrogel, H12/H13 ....................248 7.10.3 Urethane Hydrogel, H14 ......................248 7.10.4 Disulfide brigded hydrogel, H15 ..................249 List of Figures A List of Tables G Glossary I IV Abbreviations and Symbols Abbreviations abs. absolute ACN acetonitrile ACTH adrenocorticotropic hormone Ala l-alanine; (S)-2-aminopropanoic acid, A ANT [Ac-4-NO2-Phe-c(d-Cys-Tyr-d-Trp-Lys-Thr-Cys)-d-Tyr-NH2] AOAC (2-aminooxy)acetic acid Arg l-arginine; (S)-2-amino-5-guanidinovalerianic acid, R Asp l-aspartic acid; (S)-2-aminosuccinic acid, D ATR attenuated total reflection/reflectance ATRP atom transfer radical polymerization a.u. arbitrary units bl block BNCT boron neutron capture therapy Boc tert-butyloxycarbonyl Boc-AOAc N -Boc(2-aminooxy)acetic acid BocPip N -tert-butyloxycarbonylpiperazine bp.
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