| ABSTRACT | 第7-9页 |
| 摘要 | 第10-19页 |
| CHAPTER 1 GENERAL REVIEW (BACKGROUND) | 第19-35页 |
| 1.1. Incidence of Cancer | 第19页 |
| 1.2. Diagnosis of Cancer: Biomedical Imaging Techniques | 第19-22页 |
| 1.2.1 Magnetic resonance imaging (MRI) | 第19-20页 |
| 1.2.2 Fluorescence Imaging (FI) | 第20-21页 |
| 1.2.3. Multimodal Imaging | 第21-22页 |
| 1.3. Chemotherapy in Cancer Treatment | 第22-23页 |
| 1.3.1 Side Effect of Cancer Chemotherapy | 第22-23页 |
| 1.3.2 Chemoresistance in cancer therapy | 第23页 |
| 1.4. Metabolism of Cancer | 第23-26页 |
| 1.5. Mitochondria are the main Producers of ATP and ROS, and Initiators of Cell Death | 第26-29页 |
| 1.5.1 ATP Production of Mitochondria | 第26-27页 |
| 1.5.2 Regulation of Apoptosis by Mitochondria . | 第27-28页 |
| 1.5.3 Regulation of Autophagy by Mitochondria | 第28页 |
| 1.5.4 Regulation of Glycolysis by Mitochondria | 第28页 |
| 1.5.5 Mitochondrial Dysfunction Promotes Glycolysis | 第28-29页 |
| 1.5.6 Mitochondrial Dysfunction Promotes Excessive ROS Generation | 第29页 |
| 1.6. Targeting Mitochondria: An Important Strategy to Induce Cancer Death | 第29-31页 |
| 1.7. Manganese Compounds: Preferred Choice for Cancer Treatment and Diagnosis | 第31-33页 |
| 1.7.1 The Anticancer Activity of Manganese compounds | 第31-32页 |
| 1.7.2 The Use of Manganese compounds in Imaging | 第32-33页 |
| 1.8. Statement of Problem and Hypothesis | 第33-34页 |
| 1.9. Objective of the Study | 第34-35页 |
| CHAPTER 2 Adpa-Mn selectively killed glioma cells via mitochondrial pathway | 第35-59页 |
| 2.1 Introduction | 第35-37页 |
| 2.2 Material and Methods | 第37-40页 |
| 2.2.1 Materials | 第37页 |
| 2.2.2 Cell Culture | 第37页 |
| 2.2.3 Cell viability assay | 第37-38页 |
| 2.2.4 Cell apoptosis assay | 第38页 |
| 2.2.5 Visualization of monodansylcadaverine (MDC)-labeled vacuoles | 第38页 |
| 2.2.6 GFP-LC3 plasmid transfection . | 第38页 |
| 2.2.7 Western blot analysis | 第38-39页 |
| 2.2.8 Mitochondrial membrane potential assay | 第39页 |
| 2.2.9 Measurement of intracellular ROS production | 第39页 |
| 2.2.10 Measurement of intracellular ATP | 第39-40页 |
| 2.2.11 Statistical analysis | 第40页 |
| 2.3 RESULTS | 第40-54页 |
| 2.3.1 Adpa-Mn exhibited selective inhibition on glioma cell proliferation | 第40-43页 |
| 2.3.2 Adpa-Mn depends on Tf-Tf R system for its selectivity | 第43-44页 |
| 2.3.3 Adpa-Mn induced apoptotic cell death via mitochondria pathway | 第44-46页 |
| 2.3.4 Adpa-Mn generated ROS in U251 cells | 第46-47页 |
| 2.3.5 Adpa-Mn induced mitochondrial membrane potential depolarization | 第47-49页 |
| 2.3.6 Adpa-Mn induced apoptotic cell death through mitochondrial membrane potentialdepolarization | 第49-51页 |
| 2.3.7 Adpa-Mn decreased ATP production in U251 cells | 第51-52页 |
| 2.3.8 Adpa-Mn induced protective autophagy in glioma cells | 第52-54页 |
| 2.4 DISCUSSION | 第54-57页 |
| 2.5 CONCLUSION | 第57-59页 |
| CHAPTER 3 m-BDA inhibited LDH-A and induced mitochondria-mediated apoptosis in cancer cells | 第59-74页 |
| 3.1 INTRODUCTION | 第59-60页 |
| 3.2 MATERIALS AND METHODS | 第60-63页 |
| 3.2.1 Cell lines and cell culture | 第60页 |
| 3.2.2 Chemicals and reagents | 第60页 |
| 3.2.3 Cell proliferation assay | 第60-61页 |
| 3.2.4 Cellular uptake and imaging | 第61页 |
| 3.2.5 Western blot analysis | 第61页 |
| 3.2.6 Flow cytometry assay | 第61-62页 |
| 3.2.7 Mitochondrial membrane potential assay | 第62页 |
| 3.2.8 Measurement of intracellular ROS production | 第62页 |
| 3.2.9 Detection of LDH Activity | 第62页 |
| 3.2.10 Statistical analysis | 第62-63页 |
| 3.3 RESULTS | 第63-71页 |
| 3.3.1 m-BDA selectively inhibited cancer cell growth | 第63-65页 |
| 3.3.2 m-BDA was located in the cytosol of the cell | 第65-66页 |
| 3.3.3 m-BDA induced apoptotic cell death | 第66-67页 |
| 3.3.4 m-BDA induced apoptotic cell death by generation of reactive oxygen species(ROS) | 第67-68页 |
| 3.3.5 m-BDA-induced mitochondrial membrane potential depolarization contributed toapoptotic cell death.. | 第68-69页 |
| 3.3.6 m-BDA induced inhibitory effect on LDH-A in SMMC-7721 cells | 第69-70页 |
| 3.3.7 m-BDA exhibited higher anti-proliferative activity on cancer cells in hypoxicconditions than in normoxic conditions | 第70-71页 |
| 3.4 DISCUSSION | 第71-73页 |
| 3.5 CONCLUSION | 第73-74页 |
| CHAPTER 4 A manganese nanoparticle, PEG-Mn-BDA, inhibited LDH-A, induced mitochondria-mediated apoptosis and enhanced fluorescent and magnetic resonance imaging | 第74-98页 |
| 4.1 INTRODUCTION | 第74页 |
| 4.2 Materials and Methods | 第74-79页 |
| 4.2.1 Chemicals and Reagents | 第74-75页 |
| 4.2.2 Cell lines and cell culture | 第75页 |
| 4.2.3 Animal experiment | 第75-76页 |
| 4.2.4 Synthesis of PEG-Mn-BDA .. | 第76页 |
| 4.2.5 Characterization of PEG-Mn-BDA | 第76-77页 |
| 4.2.6 Cell proliferation assay | 第77页 |
| 4.2.7 Cellular uptake and imaging .. | 第77-78页 |
| 4.2.8 Western blot analysis | 第78页 |
| 4.2.9 Mitochondrial membrane potential assay | 第78页 |
| 4.2.10 Measurement of intracellular ROS production | 第78-79页 |
| 4.2.11 Detection of LDH Activity | 第79页 |
| 4.2.12 Statistical analysis | 第79页 |
| 4.3 RESULTS | 第79-95页 |
| 4.3.1 Synthesis and characterization | 第79-82页 |
| 4.3.2 PEG-Mn-BDA significantly and selectively inhibited cancer cell growth | 第82-83页 |
| 4.3.3 PEG-Mn-BDA exhibited apparent higher anti-proliferative activity than m-BDA | 第83-84页 |
| 4.3.4 PEG-Mn-BDA exhibited apparent better selectivity than m-BDA | 第84-85页 |
| 4.3.5 PEG-Mn-BDA induced both fluorescence and magnetic resonance imaging | 第85-86页 |
| 4.3.6. PEG-Mn-BDA induced apoptotic cell death | 第86-87页 |
| 4.3.7 PEG-Mn-BDA induced apoptotic cell death through generation of ROS | 第87-89页 |
| 4.3.8 PEG-Mn-BDA induced apoptosis through mitochondrial pathway | 第89-91页 |
| 4.3.9 PEG-Mn-BDA exhibited an inhibitory effect on LDH-A activities in SMMC-7721cells | 第91-92页 |
| 4.3.10 SMMC-7721 cells are more sensitive to PEG-Mn-BDA in hypoxic conditions thanin normoxic conditions | 第92-93页 |
| 4.3.11 PEG-Mn-BDA selectively inhibited tumor growth in vivo | 第93-95页 |
| 4.4 DISCUSSION | 第95-97页 |
| 4.5 CONCLUSION | 第97-98页 |
| CHAPTER 5 | 第98-100页 |
| 5.1 MAIN CONCLUSIONS | 第98-99页 |
| 5.2 MAIN INOVATIONS | 第99页 |
| 5.3 RESEARCH PROSPECTS | 第99-100页 |
| REFERENCES | 第100-115页 |
| PUBLICATIONS | 第115-116页 |
| LIST OF ABBREVIATIONS | 第116-120页 |
| LIST OF FIGURES | 第120-123页 |
| LIST OF TABLES | 第123-124页 |
| ACKNOWLEDGEMENT | 第124页 |
