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Protease Activatable Peptide Depot for Photodynamic Therapy and Riboflavin-Induced Hyaluronic acid/Peptide Hydrogel for Bio-Applications : 단백질 분해효소에 의한 활성화 펩타이드 디포를 이용한 광역동 치료 및 리보플라빈에 의한 히알루론산/펩타이드 하이드로젤의 생물의학적 응용

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dc.contributor.advisor이윤식-
dc.contributor.author박성준-
dc.date.accessioned2018-05-28T16:31:39Z-
dc.date.available2018-05-28T16:31:39Z-
dc.date.issued2018-02-
dc.identifier.other000000151168-
dc.identifier.urihttps://hdl.handle.net/10371/140765-
dc.description학위논문 (박사)-- 서울대학교 대학원 : 공과대학 화학생물공학부, 2018. 2. 이윤식.-
dc.description.abstractPeptides are widely studied in various biological applications because of their natural origins, biocompatibility, and diverse functions. One of the most common researches performed using peptides is associated with drug delivery to cancer. These include various functional peptides such as RGD or MMP-7, which are related to overexpressed factors concerning cancer. Recently, structural features of peptides are gaining great interest, where delicate organization could be achieved by specifically designed sequences. These peptides could be utilized in the fabrication of various biomaterials such as hydrogels.
In chapter 1, a cyclic internalizing RGD peptide (iRGD) derivative (Ppa-iRGDC-BK01) that self-aggregates into a molecular depot was applied to photodynamic therapy (PDT). Ppa-iRGDC-BK01 is designed as an in-situ self-implantable photosensitizer so that it forms depot by itself upon injection, and its molecular activities (cancer cell internalization and photosensitization) are activated by sustained release and tumor-selective proteolytic/reductive cleavage of the iRGD segment. It turned out that the self-aggregation of Ppa-iRGDC-BK01 into depot exerts a multiple-quenching effect to effectively prevent nonspecific phototoxicity and photobleaching, while allowing for its sustained release, tumor accumulation and tumoral activation of photosensitivity over time. Such a single-component photosensitizing molecular depot approach, combined with a strategy of tumor-targeted therapeutic activation, opens up a new way to safer and more precise repetition of PDT through single injection and multiple irradiations.
In chapter 2, Tyramine conjugated hyaluronic acid (HA-Ty) was rheometrically modulated with tyrosine rich peptides (TRP) in hydrogel formation, and its potential as a wound healing agent was tested. Riboflavin-sensitized photo-crosslinking was utilized as a gelation strategy, where riboflavin induces covalent linkages between the phenolic groups of conjugated tyramines under UV irradiation. TRP, as an additive, enhanced the storage modulus of the HA-Ty hydrogel because the tyrosine residues could also participate in the crosslinking with the phenol moieties of the HA-Ty. The HA-Ty/TRP hybrid hydrogels were tested as a plausible healing agent for wound injuries.
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dc.description.tableofcontentsIntroduction 1
1. Peptide linkers 2
2. Application of peptide linkers in biological probes 5
3. Application of peptide linkers in hydrogels 8
4. Research Objective 11
Chapter I. Protease Activatable Peptide Depot for Photodynamic Therapy 13
1. Introduction 14
1.1. Basic Principles of Photodynamic Therapy 14
1.2. Issues to Overcome for Effective Photodynamic Therapy 18
1.3. Cyclic iRGD Peptide for Photosensitizer Formulation as an Injectable Depot-Forming Monolith 21
1.4. Research Objective 25
2. Experimental Section 27
2.1. Chemicals and Materials 27
2.2. Synthesis of Ppa-iRGDC-BK01 and Control Peptides 28
2.3. Time Correlated Single Photon Counting (TCSPC) 31
2.4. Singlet oxygen generation 32
2.5. In vitro cellular uptake 33
2.6. In vitro dark and phototoxicity assay 34
2.7. Animal experiments 35
2.8. In vivo photodynamic therapy 36
3. Results and Discussion 38
3.1. Synthesis of Activatable Ppa-iRGDC-BK01 38
3.2. Fluorescence Activation of Ppa-iRGDC-BK01 under Laser Irradiation 41
3.3. Singlet Oxygen Generation by Ppa-iRGDC-BK01 46
3.4. Cellular Uptake and Cell Viability Under Laser Irradiation 49
3.5. Depot Formation and Sustained Release 52
3.5. Single Injection and Multiple Irradiations for PDT 55
4. Conclusion 60
Chapter II. Riboflavin-Induced Hyaluronic acid/Peptide Hydrogel for Bio-Applications 61
1. Introduction 62
1.1. Hyaluronic Acid Hydrogel for Bio-Applications 62
1.2. Riboflavin/UVA based Hydrogel Fabrication 64
1.3. Tyrosine-Rich Peptides as Modulators for HA-Ty Hydrogel 66
1.4. GHK-Cu for effective Wound Healing 67
1.4. Research Objective 69
2. Experimental Section 70
2.1. Materials and Instrumentation 70
2.2. Synthesis and Characterization of Tyramine-conjugated Hyaluronic Acid 72
2.3. Fabrication of HA-Ty Hydrogel by Riboflavin and UVA 74
2.4. In vitro Swelling & Degradation Tests 75
2.5. Rheological Analysis 76
2.6. Cytotoxicity and Cell Proliferation Assay 77
2.7. In vivo Wound Healing Experiments 79
3. Results and Discussion 81
3.1. Preparation of Tyramine-conjugated Hyaluronic Acid 81
3.2. Optimization of Hydrogel Fabrication using Riboflavin and UVA 84
3.3. Preparation of HA-Ty/TRP Hydrogel 86
3.4. Characterization of HA-Ty/TRP Hydrogel 88
3.4. Proliferation Test using Human Dermal Fibroblasts and Mesenchymal Stem Cells 93
3.5 Effects of HA-Ty/YC7 Hydrogel in Wound Healing Applications 97
4. Conclusion 103
Appendix 104
References 109
요 약 (국문 초록) 122
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dc.formatapplication/pdf-
dc.format.extent2669120 bytes-
dc.format.mediumapplication/pdf-
dc.language.isoen-
dc.publisher서울대학교 대학원-
dc.subjectPhotodynamic therapy-
dc.subjectInternalizing RGD (iRGD)-
dc.subjectActivatable photosensitizer-
dc.subjectSubcutaneous depot-
dc.subjectSustained release-
dc.subjectHyaluronic acid hydrogel-
dc.subjectTyrosine-rich peptides-
dc.subjectRiboflavin-
dc.subjectPhoto-crosslinking-
dc.subjectWound healing-
dc.subject.ddc660.6-
dc.titleProtease Activatable Peptide Depot for Photodynamic Therapy and Riboflavin-Induced Hyaluronic acid/Peptide Hydrogel for Bio-Applications-
dc.title.alternative단백질 분해효소에 의한 활성화 펩타이드 디포를 이용한 광역동 치료 및 리보플라빈에 의한 히알루론산/펩타이드 하이드로젤의 생물의학적 응용-
dc.typeThesis-
dc.contributor.AlternativeAuthorSung-Jun Park-
dc.description.degreeDoctor-
dc.contributor.affiliation공과대학 화학생물공학부-
dc.date.awarded2018-02-
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