臺灣博碩士論文加值系統

本論文的研究工作分為兩個部份：
第一部份的內容為將具有比率螢光性質的3-羥基黃酮類螢光團應用於以聚異丙基丙烯醯胺為基礎的熱感應型材料上。當環境溫度增加時，此共聚物材料Thermo-3HF 的螢光將會由原本的藍光漸漸轉為綠光，進而達到雙波長螢光輸出比率改變的效果。此材料Thermo-3HF 的比率螢光性質有效地克服了傳統單波長螢光探針於實際應用時所遭遇的問題，因此獲得高的溫度敏感度以及可逆性的訊號輸出。Thermo-3HF 的感測溫度區間經設計後介於攝氏33 至41 度間，亦大幅地提高了未來用於細胞顯影的可能性。此外，值得一提的是Thermo-3HF 於其感測區間內具有8.7 倍的比率螢光轉變倍數，此顯著的螢光顏色變化使得以肉眼辨色來區分溫度的想法具有高度的可行性。
第二部份的內容為延伸熱感應式奈米溫度計的研究。設計並合成能與過氧化氫作用的共聚合物HP-3HF，利用硼酯單元與過氧化氫氧化反應前後的結構差異，造成聚合物內部親水及疏水性質發生變化，使得外部的水大量湧入聚合物奈米顆粒內，讓聚合物的顆粒體積受到改變。此時具環境極性敏感的3-羥基黃酮螢光單元會因周圍微環境的改變而使其螢光光色產生變化，達到感應過氧化氫的能力。後續的研究更探展了此新開發的過氧化氫敏感型奈米聚合物HP-3HF作為多功能藥物傳遞載體的可能性。經測試的結果，HP-3HF奈米載體可以有效地進入RAW 264.7細胞內且具有相對低的細胞毒性，未來有機會作為一生物相容的生醫材料。此外，利用包覆尼羅紅染料的HP-3HF奈米粒子進行模擬藥物的應激釋放實驗，結果顯示HP-3HF作為過氧化氫應激型藥物傳遞載體的想法具可行性。

The studies of this thesis are divided into two parts:
Section I describes that a novel nanothermometer Thermo-3HF with self-calibrating ratiometric fluorescence readout was designed and synthesized by taking advantage of the fluorescence nature of 3-hydroxyflavones. Thermo-3HF consists of thermoresponive NIPAM unit, crosslinker MBAM unit, and environmentally-sensitive 3-HFAM fluorescent unit in a ratio of 100: 1: 1. Within a sensing temperature range of 33 to 41 oC, the fluorescence color of the Thermo-3HF nanothermometer changes from blue to green. The ratiometric change magnitude is about 8.7-fold, rendering the visual differentiation of color by the naked eyes feasible.
Section II describes the early-stage result of developing multifunctional drug delivery nanovectors. A reaction-based cross-linked polymeric nanoprobe HP-3HF with self-calibrating ratiometric fluorescence readout to selectively detect H2O2 is reported. HP-3HF nanoprobe is fabricated by hydrophobic H2O2-reactive boronic ester groups DCBE, crosslinker units HQBAE, and environmental-sensitive 3-HFAM fluorophores via miniemulsion polymerization. Upon the treatment of H2O2, the boronic esters in the polymer are cleavaged to form hydrophilic alcohols, subsequently leading to a hydrophobic/hydrophilic transition. Covalently linked 3-hydroxyflavones manifest the change in polarity as a ratiometric transition from green to blue, accompanied by a 500-fold increase in its volume. In addition, HP-3HF nanoprobe has been exploited for ratiometric glucose sensing by monitoring the H2O2 generated from the oxidation of glucose via glucose oxidase, and thus successfully distinguished between normal and pathological levels of glucose. After completing these tests, the potential of HP-3HF as a H2O2-responsive drug delivery nanovector for the remedy of cancers or inflammation-related diseases has been explored. The assessments of cellular uptake and cytotoxicity analysis of HP-3HF nanovector in RAW 264.7 macrophages confirm that HP-3HF is biocompatible and easy to enter into cells. The drug-releasing experiment of Nile Red-encapsulated HP-3HF (NR@HP-3HF) upon H2O2 stimulation also shows that HP-3HF is feasible as a controlled drug delivery nanovector.

TABLE OF CONTENTS
ABSTRACT…………………………………………………………………………i
TABLE OF CONTENTS…………………………………………………vii
LIST OF FIGURES………………………………………………………xiii
LIST OF SCHEMES………………………………………………………xxiii
LIST OF TABLES…………………………………………………………xxiv
I. Development of PNIPAM-Based Fluorescent Nanothermometers with Ratiometric Readout…………………………………………………………1
CHAPTER 1 INTRODUCTION……………………………………………………2
1.1 Stimuli-Responsive Materials……………………………………………2
1.1.1 Classification of Stimuli………………………………………………………3
1.1.2 Temperature-Responsive Polymers…………………………………………4
1.1.2.1 Thermo-Responsive Polymers Based on LCST………………………4
1.1.2.2 Thermo-Responsive Polymers Based on Amphiphilic Balance……9
1.1.2.3 Control of LCST………………………………………………………12
1.1.2.4 Thermo-Responsive Sensitivity: Inspection of Hysteresis Phenomenon…………………………………………………………15
1.2 Thermo-Responsive Nanoprobes………………………………………………17
1.2.1 Niches of Stimuli-Responsive Nanoprobes……………………18
1.2.2 Motives for Developing Thermo-Responsive Nanoprobes………………22
1.2.3 LCST-Based Nanothermometers…………………………………………23
1.3 Ratiometric Fluorescence Readout……………………………………………29
1.3.1 Advantages of Ratiometric Sensing………………………………………30
1.3.2 Double-Emitter Ratiometric System………………………………………30
1.3.3 3-Hydroxyflavones: Single-Emitter Ratiometric System…………………34
1.4 Design of PNIPAM-Based Fluorescent Nanothermometers with Ratiometric Readout…………………………………………………………………………38
1.4.1 Illustration of PNIPAM-Based Ratiometric Nanothermometers………38
CHAPTER 2 RESULTS AND DISCUSSIONS……………………………………41
2.1 Synthesis of 3-HFAM Monomer………………………………………………41
2.2 Fluorescence Behaviors of 3-HFAM Monomer in Response to Different Ratios of Water and Dimethylsulfoxide………………………………………42
2.3 General Procedures for the Preparation of 3HF-nanogel……………………43
2.4 Optimization of 3HF-nanogel…………………………………………………45
2.5 Characterization of Thermo-3HF……………………………………………46
2.5.1 NMR Analysis………………………………………………………………46
2.5.2 Particle Size and Morphology………………………………………………47
2.6 Variable-Temperature Spectroscopic Measurements………………………48
2.6.1 VT-Size by DLS Measurements……………………………………………48
2.6.2 VT-Turbidity…………………………………………………………………49
2.6.3 VT-Fluorescence……………………………………………………………50
2.7 Reversibility……………………………………………………………………53
2.8 Effect of Mixed Solvents on Characteristics of 3HF-nanogel………………54
2.9 Conclusions……………………………………………………………………58
II. Developing Novel Hydrogen Peroxide-Sensitive Nanoprobes with Ratiometric Fluorescence Readout and Exploring their Potential Applications as Multifunctional Drug Delivery System……………………59
CHAPTER 3 INTRODUCTION……………………………………………………60
3.1 Cancers and Chemotherapeutic Agents……………………………………60
3.2 Inflammation……………………………………………………………………62
3.3 Drug Delivery System………………………………………………………64
3.3.1 Prodrugs……………………………………………………………………65
3.3.2 Drug Delivery Vectors………………………………………………………68
3.3.2.1 Liposome………………………………………………………………70
3.3.2.2 Polymer-Drug Conjugates……………………………………………72
3.3.2.3 Polymeric Micelles and Polymersome………………………………73
3.3.2.4 Polymeric Nanoparticle………………………………………………75
3.4 Functional Drug Delivery System………………………………………77
3.4.1 Targeting……………………………………………………………………78
3.4.1.1 Intracellular Microenvironment of Inflammatory/Tumor Tissue…78
3.4.1.2 Passive Targeting………………………………………………81
3.4.1.3 Ligand-Assisted Targeting……………………………………………82
3.4.1.4 Triggered Targeting…………………………………………………84
3.4.2 Imaging………………………………………………………………………87
3.4.2.1 Fluorescent Imaging………………………………………………87
3.4.2.2 Contrast Imaging……………………………………………………90
3.4.3 On-Demand Drug Release………………………………………………91
3.5 Hydrogen Peroxide……………………………………………………………94
3.5.1 Biological Roles of Hydrogen Peroxide……………………………95
3.5.2 Reaction-Based Strategy in Response to H2O2……………………………98
3.5.3 Demasking of Boronic Ester in Response to H2O2……………………102
3.5.3.1 Molecular Probes……………………………………………………102
3.5.3.2 Polymeric Probes and Self-Immolative Polymers…………106
3.6 Design of H2O2-Targeting Drug Delivery System with Ratiometric Fluorescent Sensing Functionality……………………………108
3.6.1 Design…………………………………………………………109
CHAPTER 4 RESULTS AND DISCUSSIONS……………………………………113
4.1 Synthesis of H2O2-Reactive Monomers and Analogs Used for the Control Experiments……………………………………………………………………113
4.2 Selection of H2O2-Reactive Monomers for the Following Study……………114
4.3 Assessing the Applicability of 3-HF Fluorophores Used for Reaction-Based Nanoprobe to Sense H2O2…………………………………………………116
4.4 Procedures for the Preparation of HP-3HF and HPin-3HF………………118
4.5 Particle Size and Morphology………………………………………………121
4.6 Fluorescence Behaviors Upon Treatment of H2O2………122
4.6.1 pH Effects on Fluorescence Profiles…………………………………122
4.6.2 Time-Course Fluorescent Experiments…………………………………123
4.6.3 Concentration-Dependent Fluorescent Experiments……126
4.7 Volume Swelling Upon Treatment of H2O2………………………127
4.8 Structural Changes within the Polymer Probed by NMR……130
4.9 Stability of HP-3HF Emulsion Stored in Aqueous Conditions………131
4.10 Monitoring Temperature Variation During the Course of Reactions……132
4.11 Selectivity toward Other ROSs………………………………………………133
4.12 Application of HP-3HF for Glucose Sensing………………………………135
4.13 Evaluation of Controlled Release Using Nile Red as a Model Drug……139
4.14 Cellular Internalization of HP-3HF Nanoparticles………………………144
4.15 Cytotoxicity Assay…………………………………………………………146
4.16 In Vitro Sensing of Endogenous ROS……………………………………148
4.17 Conclusions…………………………………………………156
EXPERIMENTAL SECTION………………………………………………………159
REFERNCE………………………………………………………………………189
APPENDIX………………………………………………………………………209

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