A Study on the pH/Temperature-Sensitive Biodegradable Hydrogels for Controlled Protein and Drug Delivery Dai Phu Huynh The Graduate School Sungkyunkwan University Department of Polymer Science and Engineering i A Study on the pH/Temperature-Sensitive Biodegradable Hydrogels for Controlled Protein and Drug Delivery Dai Phu Huynh The Graduate School Sungkyunkwan University Department of Polymer Science and Engineering i A Study on the pH/Temperature-Sensitive Biodegradable Hydrogels for Controlled Protein and Drug Delivery Dai Phu Huynh A Dissertation Submitted to the Department of Polymer Science & Engineering and the Graduate School of Sungkyungkwan University in partial fulfillment of the requirements for the degree of Doctor of Philosophy [May 2007] ii CONTENTS List of Tables vi List of Schemes vii List of Figures viii Chapter General Introduction 1.1 Scop of this study 1.2 Background 1.2.1 Stimuli-sensitive copolymer hydrogels 1.2.1.1 Temperature-sensitive block copolymer hydrogels 1.2.1.2 pH and temperature-sensitive block copolymer hydrogels 1.2.2 Controlled drug/protein delivery .8 1.2.2.1 Controlled drug/protein delivery .8 1.2.2.2 Drug/protein release mechanisms 10 1.3 Aims and outlines of this study 13 References .15 Chapter A New pH/Temperature-Sensitive Block Copolymer Hydrogels Based on Poly(β-amino ester) 19 2.1 Introduction .19 2.2 Experimental 22 2.2.1 Materials .22 2.2.2 Synthesis of pH/temperature-sensitive PAE-PCL-PEG-PCL-PAE petablock copolymer hydrogel 22 2.2.2.1 Synthesis of temperature-sensitive PCL-PEG-PCLtriblock copolymer 22 2.2.2.2 Synthesis of acrylated PCL-PEG-PCLtriblock copolymers 23 2.2.2.3 Synthesis of pH/temperature-sensitive PAE-PCL-PEG-PCL-PAE pentablock copolymers 23 2.2.3 Characterization 25 i 2.2.3.1 1H-NMR analysis .25 2.2.3.2 GPC analysis 25 2.2.3.3 pH determination .25 2.2.3.4 Sol-gel phase transition measurement 26 2.2.3.5 Cytotoxicity evaluation 26 2.2.3.6 Storage stability .26 2.3 Results and discussions .28 2.3.1 Synthesis and characterization of block copolymers .28 2.3.2 Sol-gel phase transition diagram of triblock and pentablock copolymers .31 2.3.3 pH change of the pentablock copolymers with varying temperature .34 2.3.4 Control of Sol-gel phase transition diagram of copolymers 36 2.3.5 Cytotoxicity evaluation 43 2.3.6 Degradability evaluation 44 2.3.7 Storage stability evaluation .45 2.4 Conclusions 47 References .48 Chapter Controlled Protein Release of Poly(β-amino ester) based Block Copolymer Hydrogels .51 3.1 Introduction .51 3.2 Experimental 54 3.2.1 Materials 54 3.2.2 Synthesis of pH/temperature-sensitive block copolymer hydrogel 54 3.2.3 Characterization of copolymer 54 3.2.4 Protein loading process 54 3.2.5 Degradability evaluation of complex gel in vitro .55 3.2.6 Degradability evaluation of complex gel in vivo .55 3.2.7 Insulin releasing in vitro 56 ii 3.2.8 Study insulin release in vivo using female Sprague Dawley (SD) rats 57 3.2.9 Controlled insulin release in vivo using female Sprague-Dawley (SD) rats 58 3.2.10 Controlled insulin release using diabetic fat rats (DFR) 58 3.3 Results and discussions .62 3.3.1 Synthesis and characterization of copolymers 62 3.3.2 Change of sol-gel transition by insulin loading 63 3.3.3 Degradability evaluation of block copolymers and complex gel .63 3.3.4 Degradability evaluation of complex gel in vivo .64 3.3.5 Insulin loading and release mechanism .65 3.3.6 Insulin release in vivo 71 3.3.7 Insulin release in vivo using female Sprague Dawley (SD) rats .73 3.3.8 Controlled insulin release on DFR rats .74 3.3.9 hGH loading and release in vitro 78 3.4 Results and discussions .81 References .82 Chapter Biodegradation Rate Control of Poly(β-amino ester) based Block Copolymer Hydrogels 85 4.1 Introduction .85 4.2 Experimental 87 4.2.1 Materials 87 4.2.2 Synthesis of pH/temperature-sensitive block copolymer hydrogel 87 4.2.2.1 Synthesis of temperature-sensitive PCLA-PEG-PCLAtriblock copolymers 87 4.2.2.2 Syhthesis of acrylated PCLA-PEG-PCLAs 88 4.2.2.3 Synthesis of pH/temperature-sensitive pentablock copolymers 88 4.2.3 Characterization 90 4.2.3.1 1H-NMR and GPC analyses 90 4.2.3.2 pH determination 90 iii 4.2.3.3 Sol-gel phase transition measurement 90 4.2.3.4 Cytotoxicity evaluation .90 4.2.4 Insulin loading process 91 4.2.5 Degradability evaluation 91 4.2.6 Degradability evaluation of the complex gel in vivo 92 4.2.7 Insulin release in vitro 92 4.2.8 Storage stability 92 4.3 Results and discussions .93 4.3.1 Synthesis characterization of block copolymers .93 4.3.2 pH change of pentablock copolymers with varying temperature .97 4.3.3 Sol-sel phase transition diagrams 99 4.3.4 Cytotoxicity evaluation 105 4.3.5 Change of sol-gel transition by insulin loading 106 4.3.6 Degradability evaluation 106 4.3.7 Degradatbility of the complex gel in vivo 109 4.3.8 Insulin release in vitro .109 4.3.9 Storage stability 112 4.4 Conclusions 114 References .115 Chapter Biodegradation Rate Control of Sulfamethazine Oligomer-based Block Copolymer Hydrogels and theirs Controlled PTX delivery .117 5.1 Introduction 117 5.2 Experimental 120 5.2.1 Materials 120 5.2.2 Synthesis of OSM-based pH-sensitive block copolymer hydrogels 120 5.2.2.1 Synthesis of sulfamethazine oligomer 120 5.2.2.2 Synthesis of temperature-sensitive PCGA-PEG-PCGAtriblock copolymers 121 iv 5.2.2.3 Synthesis of pH/temperature-sensitive OSM-PCGA-PEG-PCGA-OSM pentablock copolymers 121 5.2.3 Characterization .124 5.2.3.1 1H-NMR analysis 124 5.2.3.2 GPC analysis .124 5.2.3.3 Sol-gel phase transition measurement 124 5.2.3.4 Degradability evaluation .125 5.2.4 Drug loading and release in vitro 125 5.2.5 PTX assay by HPLC .125 5.3 Results and discussions .126 5.3.1 Synthesis and characterization .126 5.3.2 Sol-gel phase transition diagrams 130 5.3.3 Sol-gel phase transition in vitro .138 5.3.4 Degradability evaluation 139 5.3.5 Drug loading and release in vitro 141 5.3.6 Storage stability 143 5.4 Conclusions 144 References .145 v List of Tables Table 2-1 Molecular weight and polydispersity of PCL-PEG-PCL triblock and PAE-PCL-PEG-PCLPAE pentablock copolymers ··················································································································30 Table 4-1 Molecular weight and polydispersity of PCLA-PEG-PCLA triblock and PAE-PCLA-PEGPCLA-PAE (CL/LA~ 2/1) pentablock copolymers ································································································97 Table 5-1 Molecular weight of sulfamethazine oligomer ·········································································································127 Table 5-2 Molecular weight and polydispersity of PCGA-PEG-PCGA triblock and OSM-PCGA-PEGPCGA-OSM pentablock copolymers ···························································································································129 Table 5-3 Sol-gel phase transitions of OSM-PCGA-PEG-PCGA-OSM copolymer solutions (concentration 20 wt%) obtain during injection testing to the environment at temperature 37 °C, and pH 8.0 and 7.4 ······································································································································································138 vi Table 5-3 shows the sol-gel transition behavior of the pentablock copolymer aqueous solution obtained during the injection experiments Based on Figures 5-7 and 9, the points at 37 °C and pH 8.0 for compositions A-1, B-1, D-1, C-1, C-2, C-2.1 (table 5-2), and the point at 37 °C and pH 7.4 of A-1, all appear outside the gel stage area of the phase diagrams Those indicate that these compositions cannot transform into the gel phase following injection under these conditions The points at 37 °C and pH 7.4 for compositions B-1, D-1, and for C-3, C-4, and C-5 (table 5-2), are all within the gel stage areas of their respective phase diagrams, and so are able to form gels when injected under these conditions However, since all of these points fall well within the border of the phase diagrams, the long-term stability of the corresponding gel stages under these conditions is not good (the gel stages of B-1, D-1, C-3, C-4, C-5 are stable for 20 days, days, day, days, and days, respectively (table 5-3)) The points at 37 °C and pH 7.4 for compositions C-2.1, C-1, C-2, C-3, C-4, and C-5 are all located at the center of the phase diagrams, so the corresponding gel stages are stable under these conditions over at least 30 days (table 5-3) 5.3.4 Degradability evaluation Figure 5-10 shows the degradation behaviors of the PCGA-PEG-PCGA and OSM-PCGA-PEG-PCGAOSM block copolymer solutions compared to those of PCLA-PEG-PCLA and OSM-PCLA-PEG-PCLAOSM at 37 °C and pH 7.4 As can be seen in this Figure 5-10, the degradation rate of OSM-PCGA-PEGPCGA-OSM is particularly fast in the early stages if compare with PCGA-PEG-PCGA That may be the result of the detaching of OSM from pentablock OSM-PCGA-PEG-PCGA-OSM copolymer under the hydrolysis of PCGA After 16 days, most of OSM was disconnected, that make OSM-PCGA-PEG-PCGA-OSM change to PCGA-PEG-PCGA Consequently, the slop of the degradation rate of pentablock copolymer is observed to slow to similar with the degradation of triblock copolymer PCGA-PEG-PCGA Interestingly, the molecular weight of these polymers was also observed to decrease after 32 days degradation OSM-PCGAPEG-PCGA-OSM demonstrated losses of 2323 compared to OSM-PCLA-PEG-PCLA-OSM, which showed losses of 998 (calculated from Figure 5-10 b), respectively Although OSM-PCGA-PEG-PCGAOSM degraded with the large amount after 32 days, the phenomenon of copolymer solution still remained as a gel phase However, the gel structure was broken after 40 days, and the phenomenon of copolymer solution changed to sol phase as a segregative phenomenon These results indicate that OSM-PCGA-PEG-PCGA- 139 OSM degrades faster than OSM-PCLA-PEG-PCLA-OSM As such, it is expected that drugs will be released faster when loaded in OSM-PCGA-PEG-PCGA-OSM compared to OSM-PCLA-PEG-PCLA-OSM Figure 5-10 Change of molecular weight with time at 37oC and pH 7.4, a) PCGA-PEG-PCGAand OSMPCGA-PEG-PCGA-OSM, b) OSM-PCGA-PEG-PCGA-OSM and OSM-PCLA-PEG-PCLA-OSM 140 5.3.5 Drug loading and release in vitro To specify the dominant factor of paclitaxel drug release from the pH/temperature-sensitive hydrogel, PTX was loaded into the OSM-PCGA-PEG-PCGA-OSM and OSM-PCLA-PEG-PCLA-OSM matrices Then the releasing of PTX from that hydrogel was studied and compared in vitro experiment Figure 5-11 shows the results for the release into the environment of the PTX, which obtained by the in vitro test method (the drug content in the polymer aqueous solution was weight percent compared to the matrix) As can be seen in Figure 5-11 a, more than 90% of the PTX was released from the OSM-PCGA-PEG-PCGA-OSM gel matrix after 20 days When a higher concentration of drug was loaded into the matrix, the amount of drug remaining in the matrix after its release was found to be higher The amount of drug remaining in the matrix 32 days after the drug release was 0.8 %, 2.8 %, and 3.5 % for the sample with a 2.5 mg/ml, mg/ml, and 10 mg/ml PTX loading in to copolymer solution (calculated from Figure 5-11 a), respectively Whereas in the case of OSMPCLA-PEG-PCLA-OSM, it takes more than 28 days to release 90% PTX from this gel matrix (Figure 5-11 b) And the PTX still remaining in the matrix after 32 days releasing is 3.3%, 5.5% and 7.7% for the samples with 2.5 mg/ml, mg/ml and 10 mg/ml PTX loading in to copolymers solution Those calculations show that PTX release from OSM-PCGA-PEG-PCGA-OSM gel matrix faster than that from OSM-PCLA-PEGPCLA-OSM When loading to these anionic matrixes, PTX was encapsulated in to the hydrophobic core OSM-PCGA or OSM-PCLA of micelles structures of that copolymer The releasing of that drug was followed by two steps Firstly, PTX escape from the micelle structure because of the PCGA/PCLA degradation/erosion After that, it releases from the gel matrixes by the diffusional moving Because of that, the releasing of PTX from these gel matrixes has closely related with their degradation Such, the release speed of the drug is depending on the degradation of copolymers The results in Figure 5-10 show that the gradation of OSM-PCGA-PEG-PCGAOSM is faster than that of OSM-PCLA-PEG-PCLA-OSM so the releasing time of drug, which was loaded into OSM-PCGA-PEG-PCGA-OSM, should be shorter than that in OSM-PCLA-PEG-PCLA-OSM The mechanism of drug loading and releasing from this type of pH/temperature-sensitive hydrogel was explained Shim et al [33] 141 Figure 5-11 Cumulative release of PTX in vitro, a) PTX release from OSM-PCGA-PEG-PCGA-OSM (C-4; PEG 1750, PCGA/PEG: 2.67/1, OSM 904) matrix, b) PTX release from OSM-PCLA-PEG-PCLAOSM (PEG 1750, PCLA/PEG: 1.89/1, OSM 1040) matrix [33] 142 5.3.6 Storage stability One of the most important properties of the biomaterial is the stability during stored time before used Because of that, the degradation of OSM-PCGA-PEG-PCGA-OSM solution (20 wt%) was investigated at several conditions and showed in Figure 5-12 It was found that the degradation slop of OSM-PCGA-PEGPCGA-OSM at °C is faster than that at °C In addition, the corresponding molecular weight of pentablock loss 1147 after months storing period It is believed that the molecular weight of OSM-PCGA-PEG-PCGAOSM remains constant over this entire month-period in aqueous solution Figure 5-12 Change of molecular weight of OSM-PCGA-PEG-PCGA-OSM (C-4; PEG1750, PEG/PCLA:1/2.67; OSM 904), which was kept as solution (20 wt%) at °C, °C and pH 8.0 over speci fied time periods 143 5.4 Conclusions OSM-PCGA-PEG-PCGA-OSM pentablock copolymers of varying PEG molecular weight and PCGA/PEG ratios were synthesized, and their pH and thermo reversible phase transition behaviors immediately following injection were investigated The typical phase diagrams exhibited a CGC, CGpH and two CGT curves The CGC and CGpH of the pH/temperature-sensitive block copolymers can be controlled by varying the ratio of hydrophobic/hydrophilic chain lengths (PCGA/PEG), the concentration of the copolymer in solution, and the molecular weight of the pH-sensitive component The CGT, and the range between the lower CGT and the upper CGT, can both be determined by the length of the hydrophilic segment (PEG) and by the concentration of copolymer in solution In other words, the gel phase zones of OSM-PCGAPEG-PCGA-OSM can be adjusted by varying the PEG molecular weight, the PCGA/PEG ratio and the concentration of the pH-sensitive block For injection purposes, the best condition for the excited gel stage of the pH/temperature-sensitive block copolymer solutions is positioned directly in the center of the gel phase area of the phase diagrams The degradation of OSM-PCGA-PEG-PCGA-OSM is notably faster than OSM-PCLAPEG-PCLA-OSM, indicating its potential for drug delivery This polymer can be kept in aqueous solution at 0oC for more 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Properties Laboratory All professors, and support staffs of School of Engineering, Sungkyungkwan University Thank you very much to my dear Vietnamese friends in SKKU for all wholehearted encouragement and advice To be grateful to my family in Vietnam, my Mum, my Dad, my sisters and my brothers, who always stand by and comfort me throughout my life CURRICULUM VITAE Personal Information: Name: Dai Phu Huynh Date of birth : January 04, 1973 Place of birth : Quang Ninh,Vietnam Marital status : Married Nationality : Vietnamese Present address : Department of Polymer Science & Engineering, Sungkyunkwan University, 300 Chunchun-dong, Jangan-gu, Suwon, Gyeonggi 440-746, Korea e-mail: huynh_daiphu@yahoo.com Education: 2004.9.~2007.8 SungkyunkwanUniversity(Ph.D.-PolymerScienceandEngineering),Korea 1998.9.~2001.9 HoChiMinh City University of Technology – University of Technology HoChiMinh City National University (M S – Department of Polymer Science and Engineering- Chemical Engineering Faculty) Vietnam 1991 ~ 1996 HoChiMinh City University of Technology (B S – Department of Polymer Science and EngineeringChemicalEngineeringFaculty),Vietnam Dissertation Titles: M.S Thesis: Research on high temperature resistant composite materials based on Epoxy Novolack 438 Ph.D Dissertation: AStudy on the pH/Temperature-sensitive Biodegradable Hydrogels for Controlled Protein and Drug Delivery Work experience: 1996 ~ 2000 Researcher, Polymer Research Center Lecturer of Chemical Faculty, HoChiMinh City University of Technology,Vietnam 2000 ~ 2004 Researcher, Polymer Research Center Lecturer of Materials Faculty, HoChiMinh City University of Technology.Vietnam List of publication and submit to be papers: D P Huynh, M K Nguyen, B S Pi, M.S Kim, S Y Chae, K C Lee, B S Kim, S W Kim and D S Lee, “Anew functionalized injectable hydrogel for controlled insulin delivery”, (Submitted to JACS) D P Huynh, B S Kim and D S Lee, “Controlled release of insulin by a new functionalized injectable hydrogel”, (Submitted to be Biomaterials) D P Huynh, M K Nguyen, M.S Kim, B S Kim and D S Lee, “pH/temperature-sensitive Injectablebiodegradable hydrogel with duo-functional of pH moiety for anionic drug/protein delivery”, (in preparation for Biomacromolecules) D P Huynh, M K Nguyen, M.S Kim, B S Kim and D S Lee, “Control of degradation rate in pH/temperaturesensitive Injectable-biodegradable hydrogel for anionic drug/protein delivery”, (in preparation for Polymer) D P Huynh, W S Shim, J H Kim and D S Lee, “pH/temperature-sensitive poly(ethylene glycol)-based biodegradable polyester block copolymer hydrogels”, Polymer, 47, 7918-7926 (2006) D P Huynh, T D Ngo, D T Nguyen and H N Nguyen, “Basic Research on synthesis of Polyimide”, TapChiHoaHoc (Chemical Journal-Vietnam), 40(4B), (2001) T D Ngo, D P Huynh, D T Nguyen and H N Nguyen, “Epoxy novolack based temperature-enduring materials”, TapChiHoaHoc (Chemical Journal-Vietnam), 40(4B), (2001) D P Huynh, H N Nguyen, M T Ton That and D T Nguyen, “Modification of vinyl ester resin with epoxydized liquid natural rubber vinyl ester”, TapChiHoaHoc (Chemical Journal-Vietnam), 35(4), 47-50 (1997) List of patents: Doo Sung Lee, Dai Phu Huynh, Min Sang Kim, Bong Sup Kim “pH & temperature-sensitive hydrogel”, Korea Patent, 10-0641270(2006) (2006.10.25) Doo Sung Lee, Woo Sun Shim, You Han Bae, Je Sun Yoo, Min Sang Kim, Dai Phu Huynh, "pH and Temperature-sensitive Hydrogels", Application No PCT/KR2005/000207 (Jan 26, 2005), Publication No WO 2005/073281 A1 (Aug 11, 2005) Doo Sung Lee, Je Sun Yoo, Dai Phu Huynh, Bong Sup Kim, Min Sang Kim, Minh Khanh Nguyen, " Novel pH and Temperature-Sensitive Block Copolymer Hydrogels and using it the same", Application No PCT/KR2006/001185 (Mar 31, 2006), Publication No WO 2006/109945 A1 (Oct 19.2006) Doo Sung Lee, Woo Sun Shim, You Han Bae, Je Sun Yoo, Min Sang Kim, Dai Phu Huynh, "pH and Temperature-sensitive Hydrogels", USA 2006/USP10/590959, Jan.26, 2005 (Application) Doo Sung Lee, Woo Sun Shim, You Han Bae, Je Sun Yoo, Min Sang Kim, Dai Phu Huynh, "pH and Temperature-sensitive Hydrogels", China2006-80010601.X, Sep.29, 2006 (Application) Doo Sung Lee, Woo Sun Shim, You Han Bae, Je Sun Yoo, Min Sang Kim, Dai Phu Huynh, "pH and Temperature-sensitive Hydrogels", Japan 2007-58882, Mar.8, 2007 (Application) Doo Sung Lee, Woo Sun Shim, You Han Bae, Je Sun Yoo, Min Sang Kim, Dai Phu Huynh, "pH and Temperature-sensitive Hydrogels", EU(31 countries), EP 05 710 824.3, Jan.26, 2005 (Application) Doo Sung Lee, Woo Sun Shim, You Han Bae, Je Sun Yoo, Min Sang Kim, Dai Phu Huynh, “Temperature and pH-sensitive Hydrogels”, Korea Patent 10-0641270 (2006) (2006.10.25) Doo Sung Lee, Woo Sun Shim, Dai Phu Huynh, Min Sang Kim, Minh Khanh Nguyen, Bong Sup Kim, “Novel Temperature and pH-sensitive block copolymer and application of polymer-hydrogels“, Korea Patent 10-0665672 (2006) (2006 12 29) 10 Doo Sung Lee, MinutesSang Kim, Dai Phu Huynh, Bong Su Pi, Minh Khanh Nguyen, Bong Sup Kim, Su Young Jae, “Temperature and pH-sensitive block copolymer apply for injectable drug carrier and drug delivery application”, Korea patent application 2007-0015586 (2007.2.14) List of presentations: International Conference – presentations D P Huynh, D S Lee, "Novel pH/temperature-sensitive hydrogels of biodegradable polymer block copolymer based on poly(β-amino ester)", 7th Asian Symposium on Biomedical Materials (ASBM-7), August 22, 2006, Jeju Island, Korea D S Lee, D P Huynh, "Novel pH/temperature-sensitive hydrogels for injectable drug delivery system", 7th Asian Symposium on Biomedical Materials (ASBM-7), August 23, 2006, Jeju Island, Korea (Invited Talk) D P Huynh, D S Lee, "Novel pH/temperature-sensitive hydrogels of poly(ethylene glycol)-poly(caprolactone)poly(β-amino ester) (PAE-PCLA-PEG-PCLA- PAE) biodegradable polyester block copolymer", IUPAC International Symposiumon Advanced Polymer for Emerging Technologies, October 13, 2006,Busan, Korea B S Pi, D P Huynh, B S Kim, S Y Chae, K C Lee, D S Lee, "Insulin release of novel injectable pH-sensitive hydrogels", 13th International Symposium on Recent Advances in Drug Delivery Systems, February 26-28, 2007, Salt Lake City, USA D P Huynh, B S Pi, B S Kim, D S Lee, "Injectable pH/Temperaturte-Senstive Hydrogel for PeptideandProteinDelivery ", 34thAnnual Meeting & Exposition, Controlled Release Society, Long Beach, California, July 7-11, 2007, USA M K Nguyen, B S Pi, D P Huynh, B S Kim, D S Lee, " Molecular Design of Novel Biodegradable pH/Temperature-Sensitive Block Copolymer Hydrogel ", 34th Annual Meeting & Exposition, Controlled Release Society, Long Beach, California, July 7-11, 2007, USA D P Huynh, B S Kim, D S Lee, “cationic injectable biopolymer hydrogel for controlled protein and drug delivery “, 10th Conference on Material Science & Technology (10thCMST) HoChiMinh City, October 25-26, 2007, Vietnam Domestic Conference – presentations Huu Nieu Nguyen, Minh Tan Ton That, Dac Thanh Nguyen, Dai Phu Huynh, Thi Thai Ha La, Thanh Chau Nguyen, Tri Dung Ngo, Thanh Nhan Chau, “Composite material produced from carbon fibre-epoxy AP modified by ESO”, Scientific Conference, HoChiMinh City Univ of Technology-Ministry of Education, July 1999, Vietnam Tri Dung Ngo, Dai Phu Huynh, Dac Thanh Nguyen, Huu Nieu Nguyen, “Epoxy novolack clay-based high temperature endunring materials”, Scientific Conference, HoChiMinh City Univ of Technology-Ministry of Education, April 2002, Vietnam Dai Phu Huynh, Tri Dung Ngo, Dac Thanh Nguyen, Huu Nieu Nguyen, “To survey the influence of some nano clays on polyimide films”, Scientific Conference, HoChiMinh City Univ of Technology-Ministry of Education, April 2002, Vietnam Dai Phu Huynh, Doo Sung Lee, “pH and temperature-sensitive hydrogel of poly(ethylene glycol) biodegradable block copolymer”, Korea Polymer Association Symposium, April 14, 2005 Dai Phu Huynh, Doo Sung Lee, “Novel pH and temperature-sensitive hydrogels of poly(ethylene glycol)-poly(εcaprolactone)-poly(D,L lactide)-poly(β-amino ester) (PAE-PCLA-PEG-PCLA-PAE) biodegradable polyester block copolymer", 2005 Korea Biomaterials Society Symposium, October 01, 2005, Korea Dai Phu Huynh, Doo Sung Lee, “Poly(ethylene glycol)- poly(ε-caprolactone)-poly(β-amino ester) pentablock copolymer hydrogel as a pH/temperature-sensitive biodegradable polymer" 2005 Korea Polymer Society Symposium 3PS-139, October 14, 2005, Korea Dai Phu Huynh, Doo Sung Lee, “pH and temperature-sensitive hydrogels of poly(ethylene glycol) and poly(βamino ester)”, 2005 Korea Chemical Society Symposium P-Polymer-55, October 21, 2005, Korea Dai Phu Huynh, Doo Sung Lee, “Novel pH/ temperature-sensitive hydrogels of biodegradable polyester block copolymer based on poly(β-amino ester)", 2006 2005 Korea Polymer Society Symposium 3PS-196, April 07, 2006, Korea Dai Phu Huynh, Doo Sung Lee, “Injectable pH/temperature-sensitive hydrogel for protein delivery", 2007 Korea Polymer Society Symposium 1PS-140, April 12, 2007, Korea [...]... Because of the standard treatment methods, which were used to treatment for patients such as parenteral injection, oral, and drug transfusion through vein, show the disadvantages in the controlled release of drug /protein because of the enzymatic dehydration in the gastric fluid, and the limitation of the therapeutic concentration range of the drug /protein during treatment Such that, the controlled drug /protein. .. use a functional group which could make a strong reversible linkage with the drug /protein to allow for a predictable and customizable loading and release In this study, the challenger of molecular design of novel pH and temperature- sensitive hydrogels is polymer and drug (special for ionic drug) should compatibility We focused on the synthesis, characterization and evaluation of the materials As such,... several elements, for instance: pore size of hydrogels, the hydrophobicity, the presence of some specific function that make a particular interaction between the matrix and drug, and the controlling of the degradation of the biodegradable hydrogels 1.2.2.2 Drug /protein release mechanisms As discussed above, hydrogels have many advance properties that make them useful in drug delivery applications The. .. [6] K Zhang, X Y Wu, J Control Release, 80, 169 (2002) [7] T Uchiyama, Y Kiritoshi, J Watanabe, K Ishihara, Biomaterials, 24, 5183 (2003) [8] M Morishita, T Goto, N A Peppas, J I Joseph, M C Torjman, C Munsick, K Nakamura, T Yamagata, K Takayama ,A M Lowman, J Control Release, 97, 115 (2004) [9] T Yamagata, M Morishita, N J Kavimandan, K Nakamura, Y Fukuoka, K Takayama, N A Peppas, J Control Release, 112,... (PEO-P(DLLA/GA)) [12-14], and PEG-grafted chitosan [15] are common biodegradable systems for loading and releasing drug Aqueous solutions of these polymers can be prepared at low temperature, thereby allowing safe incorporation of bioactive molecules Aqueous solutions of these polymers are injectable at low temperature and form a gel at body temperature However, those polymers have some disadvantages in drug. .. copolymer hydrogels is also studied by direct contact method to check the biocompatibility property The second is to examine the formation of ionic complex between hydrogels and drug and protein after injection into the body The positive charge of ionized PAE block was used to encapsulation many specific drug such as protein PAE as the ionization stage has positive charges, and it can form the complexes... temperature- sensitive triblock copolymer made of F127, and Ais an outer cationic block pH- sensitive moiety The pentablock copolymers were synthesized by combination reaction between F127 and pH- sensitive moieties made of PDEAEMA and PDMAEMA [37,38] The 5 PDEAEMA-Pluronic-PDEAEMA and PDMAEMA-Pluronic-PDMAEMA aqueous solutions exhibited a closed-loop sol-gel-sol transition, which depend on the change... Biodegradable hydrogels have been interested as an attractive insulin formulation because they have many advantages such as biocompatibility and high responsibility for specific factors The important advantage of the drug release from the hydrogels is that could be controlled by several elements, for instance pore size of hydrogels, the hydrophobicity, the presence of some specific function that make a particular... PAE has positive charges; it could constitute a complexation with protein or anionic drugs by ionic union The new concept is using PAE as a functional group with two assignments, the first is a pH- sensitive block and the second is that it can make powerful linkages with protein or anionic drugs, to become a pH/ temperature- sensitive injectable pentablock copolymer hydrogels The material relies not only... this study The aims of this study are as follows: The first is to develop a new temperature /pH- sensitive block copolymer hydrogels to apply controlled drug and protein delivery systems These hydrogels consist of pH- sensitive block and the temperature- sensitive block to form pH/ temperature- sensitive block copolymers These copolymers are responsive to both temperature and pH, and its sol-gel transition