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국소항암치료를 위한 기능성 주사제의 약물전달

Injectable and functionalized drug depot for localized cancer therapy

초록/요약

Over the past decades, drug delivery systems have been studied, various formulations was particulate carriers, hydrogel based on polymer, lipids etc. for supporting safe and effective treatment of different diseases. However, conventional drug delivery systems remained several problems such as quick initial release, cytotoxicity in vivo and cannot fulfill the needs of biomedical research. Therefore, advanced drug delivery strategy need to be maintained plasma therapeutic drug concentrations at therapeutic range for longer periods of time. In this study, a multi-drug delivery system carried to target site therapeutic drug using combinational injectable formulation in vivo, has been reported. Chapter 1 describes general introduction about background of the research, overall drug delivery systems and combination therapy for cancer treatment. Chapter 2 illustrates the preparation of multi-formulations using microcapsule and injectable hydrogels to achieve desired therapeutic range for over a specific period of time. Injectable multi-formulations were prepared by mixing BSA-FITC encapsulated PLGA microcapsules and chitosan, Pluronic®, or methoxy poly(ethylene glycol)-b-poly(3-caprolactone) (MPEG-b-PCL) hydrogel. All multi-formulations were prepared in solutions and formed a gel state after injection into a rat. Monitoring in vivo BSA-FITC release, demonstrated that the initial burst release of BSA-FITC was retarded by injectable hydrogels. In this study, the bioavailability of BSA-FITC from multi-formulations was found to depend on the viscosities of injectable hydrogels. Consequently, the viscosity of the injectable hydrogels was considered as an important factor influencing the initial burst and duration of BSA-FITC release. Chapter 3 derails the combinational chemotherapy via intratumoral injection of doxorubicin (Dox) and 5-fluorouracil (Fu) using the developed combinational formulation of hydrogel and microcapsule in chapter 2., to enhance the efficacy and reduce the toxicity of systemically administered Fu and Dox in cancer patients. As the key concept of the research, mixture formulations of Dox-loaded microcapsules (Dox-M) and Fu-loaded Pluronic® hydrogels (Fu-H) or Fu-loaded diblock copolymer hydrogels (Fu-HC) have been employed as drug depots. The in vitro and in vivo drug depot was designed as a formulation of Dox-M dispersed inside an outer shell of Fu-HP or Fu-HC after injection. After intratumoral injection, Dox-M/Fu-HC produced higher inhibition effects among tumor growth than that by Dox-M/Fu-HP, while Dox-M had the weakest inhibitory effects of the tested treatments. In conclusion, the results of this study provide a useful experimental platform for multi-drug delivery research as injectable formulations.

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목차

CONTENTS iii
LIST OF FIGURES vii
LIST OF TABLES xii

CHAPTER 1. General introduction 1
1.1. Background of the research 2
1.2. Drug delivery systems 3
1.3. Local drug delivery system for intratumoral injection 5
1.3.1. Particulate carriers 5
1.3.2. Hydrogels 6
1.4. Combination therapy for cancer treatment 8
1.5. Strategy of this works 11
1.6. References 12

CHAPTER 2. Injectable in situ-forming hydrogels for a suppression of drug burst from drug-loaded microcapsules 17
2.1. Introduction 18
2.2. Experimental section
2.2.1. Materials 23
2.2.2. Encapsulation of BSA-FITC using a mono-axial nozzle ultrasonic atomize 23
2.2.3. Encapsulation efficiency of BSA-FITC-loaded microcapsules 24
2.2.4. Preparation of an in situ-forming hydrogel solution 25
2.2.5. Viscosity measurements 25
2.2.6. In vivo injections 26
2.2.7. Real Time in vivo fluorescence imaging 27
2.2.8. Scanning electron microscopy in vitro and in vivo 28
2.2.9. Fluorescence imaging of the removed depots 28
2.2.10. Histological analysis 29
2.3. Results
2.3.1. Preparation of BSA-FITC-loaded microcapsules 31
2.3.2. Preparation of in situ-forming hydrogels 31
2.3.3. BSA-FITC release in vivo 35
2.3.4. In vivo fluorescence imaging 39
2.3.5. Morphology of the in vivo microcapsules 40
2.3.6. Host tissue response 43
2.4. Discussion 47
2.5. Conclusion 51

CHAPTER 3. Synergistic anti-tumor activity of combinational intratumoral injection of doxorubicin and 5-fluorouracil 53
3.1. Introduction 54
3.2. Experimental section
3.2.1. Materials 60
3.2.2. Preparation of Dox-M 60
3.2.3. Encapsulation efficiency of the Dox-M 61
3.2.4. Preparation of Fu-loaded HC (Fu-HC) and Fu-loaded HP (Fu-HP) hydrogels 61
3.2.5. Preparation of the Dox-M/Fu-HC and Dox-M/Fu-HP mixtures 62
3.2.6. Viscosity measurements 62
3.2.7. In vitro release 63
3.2.8. In vitro antitumor activity 63
3.2.9. In vitro fluorescent microscopy images 65
3.2.10. In vivo antitumor activity 65
3.2.11. Histological analysis 68
3.2.12. Statistical analysis 70
3.3. Results
3.3.1. Preparation of injectable formulations 71
3.3.2. Characterization of injectable formulations 73
3.3.3. In vitro Dox and Fu release 78
3.3.4. Anti-proliferative effects of the formulations 82
3.3.5. Intratumoral injection 86
3.3.6. Biodistribution of Dox and Fu 90
3.3.7. Histology studies 93
3.4. Discussion 100
3.5. Conclusion 102

REFERENCES 103
LIST OF PUBLICATIONS 109
LIST OF PRESENTATIONS 114
LIST OF PATENTS 117

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