Dual Responsive Hydrogels Based on ABC Triblock Polymers A DISSERTATION SUBMITTED TO THE FACULTY OF UNIVERSITY OF MINNESOTA BY Isha Koonar IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY Dr. Ronald A. Siegel March, 2014 Copyright © Isha Koonar, University of Minnesota, 2014 Acknowledgements I would like to thank my advisor, Dr. Ron Siegel, for his guidance that helped me pursue doctoral research. I thank Marie Gaumet for her help with the PNIPAm- P(NIPAm-co-AA)-PDEAm triblock work. I am grateful to Dr. Dave Giles, at the UMN Polymer Characterization Facility, for his help and guidance with rheology experiments. NMR experiments were performed at the Institute of Therapeutic Discovery and Development (ITDD) at the University of Minnesota. I am grateful to Prof. Tim Lodge and Prof. Marc Hillmyer for their valuable input and access to lab facilities. I am also thankful to Dr. Tushar Navale and Prof. Theresa Reineke for their help with performing reactivity ratio studies. Thanks to MRSEC program of the National Science Foundation (Award DMR-0819885) at the University of Minnesota for funding my thesis work. I am grateful to my family and friends for their support and encouragement for my graduate education. i Dedication Dedicated to my family, for their inspiration, love and trust. ii Abstract Polymers based on PNIPAm and PDEAm have great utility in injectable biomedical applications as they exhibit inverse phase solubility at transition temperatures between room temperature and physiological temperature. The aim of this study was to design polymers that would lead to physical gels at elevated temperatures. Two polymer systems were studied, one a triblock poly(ethylene-alt-propylene)- b-poly(ethyleneoxide)-b-poly(N-isopropyl acrylamide-co-acrylic acid), PEP-PEO- P(NIPAm-co-AA), or PO(N/A) triblock. This construct comprised of a hydrophobic PEP and a hydrophilic PEO mid block. The third block was based on PNIPAm, a thermoresponsive polymer exhibiting inverse phase solubility at a temperature of 32 C. PNIPAm was substituted with AA to render the block dual temperature and pH responsive. The other triblock PNIPAm-P(NIPAm-co-AA)-PDEAm [(PN(N/A)D] comprised thermoresponsive blocks with the midblock being both temperature and pH responsive. PDEAm exhibited an LCST, 30 C, close to that of PNIPAm. The triblocks were designed with the intent that on heating, the reduced solubility of the side blocks would cause the polymer to self assemble resulting in polymer aggregation/gelation. The polymers were synthesized by RAFT polymerization and anionic polymerization. Polymer association was studied by DLS, UV spectroscopy and rheology. Greater success was found with the PO(N/A) triblocks in achieving gelation at a critical temperature at low pH, than for the PN(N/A)D system, perhaps due to differences in the self assembly mechanisms. iii Table of Contents List of Tables viii List of Figures ix List of Schemes xiv Chapter I. Background 1.1. Block polymers 1 1.2. Stimuli responsive polymers 2 1.2.1. Thermoresponsive polymers 4 1.2.2. pH responsive polymers 7 1.2.3. Dual responsive polymers 7 1.3. Block polymer assemblies 1.3.1. Self Assembled monolayers 8 1.3.2. Polymer micelles 10 1.3.3. Vesicles 13 1.3.4. Hydrogels 15 1.4. Stimuli responsive gels based on triblock polymers 16 1.5. Polymer synthesis: RAFT polymerization 19 1.6. Motivation 21 1.7. Thesis outline 25 Chapter II. ABC Triblock Terpolymers Exhibiting Both Temperature and pH-sensitive Micellar Aggregation and Gelation in Aqueous Solution 2.1. Extract 27 iv 2.2. Introduction 28 2.3. Experimental Section 2.3.1. Materials 32 2.3.2. Synthesis of PO(N/A) triblock terpolymers 33 2.3.3. Reactivity ratios 34 2.3.4. Sample preparation 35 2.3.5. Dynamic light scattering 36 2.3.6. Rheology 36 2.4. Results 2.4.1. Synthesis of PO(N/A) triblock terpolymers 37 2.4.2. Micellar aggregation of PO(N/B) and PO(N/A) triblock 38 terpolymers 2.4.3. Micellar aggregation of PO(N/A) terpolymers as a function of pH 41 2.4.4. Gelation of PO(N/A) triblock terpolymers 44 2.5. Discussion 46 2.6. Conclusions 49 2.7. Supporting Information 51 Chapter III. Synthesis and Characterization of Stimuli Responsive Triblock Terpolymers 3.1. Extract 64 3.2. Introduction 65 3.3. Experimental Section 3.3.1. Materials 67 3.3.2. ABC triblock synthesis 68 v 3.3.3. Homopolymer and block polymer characterization 70 3.3.4. Thermo and pH sensitivity study 71 3.4. Results 3.4.1. Molecular weight, polydispersity 72 3.4.2. Monomer conversion 72 3.4.3. Acrylic acid percentage 73 3.4.4. Cloud point determination 74 3.4.5. Aggregate and micelle diameters 80 3.5. Discussion and Conclusion 81 3.6. Supporting Information 86 Chapter IV. Temperature and pH responsive ABC triblock polymers 4.1. Extract 93 4.2. Introduction 94 4.3. Experimental Section 4.3.1. Materials 97 4.3.2. Polymer synthesis 98 4.3.3. 1H-NMR spectroscopy 99 4.3.4. UV-Vis spectroscopy 99 4.3.5. GPC 100 4.3.6. Sample preparation 100 4.3.7. Dynamic mechanical analysis 100 4.4. Results 4.4.1. Molecular weight and polymer composition 101 vi 4.4.2. Polymer solution behavior 104 4.4.3. Dynamic mechanical analysis 105 4.4.4. Solution behavior of ABA triblock 107 4.4.5. Differences between ABA and ABC 109 4.5. Discussion 111 4.6. Conclusions 114 4.7. Supporting Information 116 Chapter V. Summary and Future Direction 5.1. Summary 124 5.2. Future direction 127 Bibliography 130 vii List of Tables Table 2.1. Molecular characteristics of PO(N/B) and PO(N/A) block polymers 35 Table 2.2. NIPAm:tBA ratios in the feed and polymer by free radical 55 polymerization Table 2.3. Hydrodynamic radii (R ) at 25 °C and transition temperatures (T) 56 h t of PON(N/B) and PO(N/A) micelles Table 3.1. Molecular weight, polydispersity and monomer conversion of the 73 polymeric blocks Table 3.2. Acrylic acid content in B block 74 Table 4.1. Molecular weight characteristics of PN(N/A)D and PN(N/A)N 102 Table 4.2. Molecular weight estimation: comparison of Universal Calibration 122 vs Refractive Index increment (dn/dc) viii