Cathepsin B-Specific Prodrug Nanoparticles to Overcome Tumor Heterogeneity = 종양 이질성 극복을 위한 암 특이적 항암 나노 약물 전구체

목차 (Table of Contents)

• Chapter 1. Introduction 1
• 1.1. General introduction 1
• 1.2. Enhanced Permeability and Retention (EPR) Effect and Nanoparticles in Cancer Research and Drug Delivery 2
• 1.3. Enzyme-activated carrier free prodrug NPs for targeting tumor tissue 3
• 1.4. Self-Assembled Cathepsin B-activable Carrier-Free Prodrug Nanoparticles 4
• 1.5. Cancer-Specific Prodrug as an ICD-inducing agent that enhance immune checkpoint blockade 7
• 1.6. Uncategorized References
• Chapter 2. Intraperitoneal Chemotherapy for Ovarian Cancer using Cathepsin B-Specific Doxorubicin Prodrug Nanoparticles 14
• 2.1. Introduction 14
• 2.2. Materials and Methods 18
• 2.2.1. Materials 18
• 2.2.2. Synthesis of cathepsin B-specific doxorubicin prodrug nanoparticles (PNPs) 19
• 2.2.3. Characterization of cathepsin B-specific doxorubicin prodrug nanoparticles (PNPs) 19
• 2.2.4. Western blot 20
• 2.2.5. Cellular uptake of PNPs in cancer cells and normal cells 21
• 2.2.6. Cytotoxicity assay 21
• 2.2.7. Pharmacokinetics/pharmacodynamics (PK/PD) study 22
• 2.2.8. Histological assay 22
• 2.2.9. Animals 23
• 2.2.10. Biodistribution of PNPs in PC models 24
• 2.2.11. In vivo anticancer efficacy studies 25
• 2.2.12. Blood analysis 26
• 2.2.13. Statistics 27
• 2.3. Results 28
• 2.3.1. Characterization of cathepsin B-specific doxorubicin prodrug nanoparticles (PNPs) 28
• 2.3.2. In vitro cancer cell-specific cytotoxicity of PNPs. 37
• 2.3.3. In vivo pharmacokinetics/pharmacodynamics (PK/PD) of intraperitoneally administered PNPs in normal mice 44
• 2.3.4. Dierct penetration and systemic blood vessel-associated accumulation of PNPs in peritoneal carcinomatosis models. 47
• 2.3.5. Anticancer efficacy of intraperitoneal chemotherapy with PNPs in POX and PDX models. 56
• 2.3.6. In vivo toxicity studies of IP injected PNPs in POX mice. 72
• 2.4. Conclusion 80
• 2.5. Reference
• Chapter 3. Combination of cancer-specific prodrug nanoparticles with Bcl-2 inhibitor to overcome acquired drug resistance. 84
• 3.1. Introduction 84
• 3.2. Materials and Methods 89
• 3.2.1. Materials 89
• 3.2.2. Preparation of cancer-specific DOX prodrug nanoparticles (PNPs) 90
• 3.2.3. Cellular uptake mechanism of PNPs in a cell culture system 91
• 3.2.4. Western blot analysis of Bcl-2 expression in a cell culture system 92
• 3.2.5. Cytotoxicity assays of combination treatment with PNPs and Navitoclax 93
• 3.2.6. In vivo distribution of PNPs in MDA-MB231 breast tumor-bearing mice 94
• 3.2.7. Antitumor efficacy of combined PNPs and Navitoclax treatment in MDA-MB231 breast tumor-bearing mice 95
• 3.2.8. Histological analysis 96
• 3.2.9. Blood analysis 96
• 3.2.10. Statistics 97
• 3.3. Results 98
• 3.3.1. Characterization of cancer-specific DOX prodrug nanoparticles (PNPs) 98
• 3.3.2. In vitro cellular uptake of PNPs in cathepsin B-overexpressing cancer cells. 108
• 3.3.3. In vitro cytotoxicity of combined PNPs and Navitoclax treatment 118
• 3.3.4. Tumor accumulation of PNPs in MDA-MB231 breast tumor-bearing mice 124
• 3.3.5. Antitumor efficacy of combined PNPs and Navitoclax in MDA-MB231 breast tumor-bearing mice 133
• 3.3.6. PNPs combined with Navitoclax mitigate in vivo toxic side effects of DOX 140
• 3.4. Conclusion 146
• Chapter 4. Cancer Cell-Specific and Pro-Apoptotic SMAC Peptide-Doxorubicin Conjugated Prodrug Encapsulated Aposome for Synergistic Cancer Immunotherapy 152
• 4.1. Introduction 152
• 4.2. Materials and Methods 157
• 4.2.1. Reagents 157
• 4.2.2. Preparation of cancer-specific and pro-apoptotic prodrug encapsulated Aposomes 158
• 4.2.3. Western blot 159
• 4.2.4. Cellular uptake of Aposomes 160
• 4.2.5. Cytotoxicity study 161
• 4.2.6. DAMPs analysis 161
• 4.2.7. Co-culture assays 162
• 4.2.8. Biodistribution of Aposomes in colon tumor models 163
• 4.2.9. In vivo antitumor efficacy and immune response of Aposomes 163
• 4.2.10. Statistical Analysis 165
• 4.3. Results 166
• 4.3.1. Preparation of cancer cell-specific and pro-apoptotic Aposomes 166
• 4.3.2. Cancer cell-specific and pro-apoptotic property of Aposomes in cell culture system 174
• 4.3.3. Immunogenic cell death (ICD) of Aposomes in cell culture system 183
• 4.3.4. Tumor targeting of Aposomes in colon tumor models 189
• 4.3.5. Antitumor efficacy and immune response of Aposomes in the colon tumor models 195
• 4.3.6. Combination of Aposomes and ICB therapy in the colon tumor models 207
• 4.4. Conclusion 215
• 4.5. References
• Chapter 5. Conclusion 220