Susanne Kirchhof Diels Alder Hydrogels as Intraocular Drug Delivery Systems for Antibodies PDF
Preview Susanne Kirchhof Diels Alder Hydrogels as Intraocular Drug Delivery Systems for Antibodies
Susanne Kirchhof Diels Alder Hydrogels as Intraocular Drug Delivery Systems for Antibodies Diels Alder Hydrogels as Intraocular Drug Delivery Systems for Antibodies DISSERTATION ZUR ERLANGUNG DES DOKTORGRADES DER NATURWISSENSCHAFTEN (DR. RER. NAT.) DER FAKULTÄT FÜR CHEMIE UND PHARMAZIE DER UNIVERSITÄT REGENSBURG vorgelegt von Susanne Kirchhof aus Bobingen Juli 2015 Diese Arbeit entstand in der Zeit von August 2010 bis Juli 2015 am Lehrstuhl für Pharmazeutische Technologie an der Universität Regensburg. Die Arbeit wurde von Herrn Prof. Dr. Achim Göpferich angeleitet. Promotionsgesuch eingereicht am: 31.Juli 2015 Datum der mündlich Prüfung: 09.Oktober 2015 Prüfungsausschuss: Prof. Dr. Jens Schlossmann (Vorsitzender) Prof. Dr. Achim Göpferich (Erstgutachter) PD Dr. Rainer Müller (Zweitgutachter) Prof. Dr. Sigurd Elz (Drittprüfer) V Diels Alder Hydrogels as Intraocular Drug Delivery Systems for Antibodies Die Wissenschaft fängt eigentlich erst da an, interessant zu werden, wo sie aufhört. Justus von Liebig VII Table of Contents 1 Introduction and Goal of the Thesis 1 .............................................................................................. 1.1 Introduction 2 ................................................................................................................................................... 1.2 Goal of the thesis 4 ....................................................................................................................................... 2 Hydrogels in Ophthalmic Applications 9 ......................................................................................... 2.1 Introduction 11 ................................................................................................................................................... 2.2 Methods of hydrogel preparation and properties of hydrogels 13 ................................ 2.3 Design criteria for hydrogels and challenges associated with their preparation 15 ..................................................................................................................................................... 2.4 Ophthalmic applications of hydrogels 16 ....................................................................................... 2.4.1 In situ forming hydrogels for ophthalmic drug delivery 16 ................................................ 2.4.2 Drug-eluting contact lenses 18 ................................................................................................................... 2.4.3 Tissue adhesives for ocular wound repair 21 ................................................................................. 2.4.4 Intraocular lenses 22 ........................................................................................................................................... 2.4.5 Hydrogel-based vitreous substitutes 23 .............................................................................................. 2.4.6 Intravitreal drug delivery systems 25 ................................................................................................... 2.4.7 Cell-based approaches 27 ............................................................................................................................... 2.5 Limitations of hydrogel-based drug delivery systems 29 .................................................... 2.6 Concluding remarks and future perspectives 31 ........................................................................ 3 Investigation of the Diels-Alder Reaction as a Cross-Linking Mechanism for Degradable Poly(ethylene glycol) Based Hydrogels 33 ............................................................ 3.1 Introduction 35 ................................................................................................................................................... IX Tables of Contents 3.2 Experimental Section 36 ............................................................................................................................. 3.2.1 General procedure 36 ......................................................................................................................................... 3.2.2 Materials 36 ............................................................................................................................................................... 3.2.3 Synthesis of branched PEG-amines 37 ............................................................................................... 3.2.4 Synthesis of furyl-substituted four-armed PEG 37 .................................................................... 3.2.5 Synthesis of furyl-substituted eight-armed PEG, molecular weight 10 kDa 38 3.2.6 Synthesis of furyl-substituted eight-armed PEG, molecular weight 20 kDa 38 3.2.7 Synthesis of 3,6-epoxy-1,2,3,6-tetrahydrophthalimide (ETPI) 38 ................................ 3.2.8 Synthesis of ETPI-substituted four-armed PEG 39 ................................................................... 3.2.9 Synthesis of 4armPEG10k-maleimide 39 ......................................................................................... 3.2.10 Synthesis of 8armPEG10k-maleimide 40 ......................................................................................... 3.2.11 Synthesis of 8armPEG20k-maleimide 40 ......................................................................................... 3.2.12 Preparation of Diels-Alder hydrogels 40 ........................................................................................... 3.2.13 Rheological characterization of Diels-Alder hydrogels 41 ................................................. 3.2.14 Calculation of hydrogel network mesh size 41 ............................................................................. 3.2.15 Swelling and degradation of Diels-Alder hydrogels 42 ......................................................... 3.3 Results and discussion 43 ........................................................................................................................... 3.3.1 Synthesis of furyl- and maleimide-substituted PEG-derivatives 43 ............................ 3.3.2 Rheological characterization of Diels-Alder hydrogels 43 ................................................. 3.3.3 Calculation of hydrogel network mesh size 46 ............................................................................. 3.3.4 Swelling and degradation of Diels-Alder hydrogels 48 ......................................................... 3.4 Conclusion 51 ..................................................................................................................................................... 4 New Insights into the Cross-Linking and Degradation Mechanism of Diels- Alder Hydrogels 53 .......................................................................................................................................... 4.1 Introduction 55 ................................................................................................................................................... 4.2 Experimental section 57 .............................................................................................................................. 4.2.1 Materials 57 ............................................................................................................................................................... 4.2.2 Hydrolytic stability of 8armPEG10k-maleimide 57 ................................................................. 4.2.3 Rheological characterization of DA hydrogels 58 ..................................................................... 4.2.4 Swelling and degradation of DA hydrogels 58 ............................................................................. 4.2.5 Molecular modeling studies 59 .................................................................................................................. 4.2.6 Statistical analysis 59 ........................................................................................................................................ 4.3 Results and discussion 60 ........................................................................................................................... 4.3.1 Hydrolytic stability of 8armPEG10k-maleimide 60 ................................................................. 4.3.2 Rheological characterization of DA hydrogels 61 ..................................................................... 4.3.3 Swelling and degradation of DA hydrogels 64 ............................................................................. 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