癌症治疗中纳米反应器的应用和克服肿瘤多药耐药性的新策略

声明

摘要

Abstract

Table of Content

Chapter Ⅰ：General Introduction about Therapeutic Nanoreactors and Cancer Treatment

1．1． Overview about cancer disease

1．2． Cancer therapy and treatment approaches

1．3． Nanotechnology for cancer treatment

1．4．Perspectives for therapeutic nanoreactors in cancer treatment

1．5．The problem statement of this study

1．6．The hypothesis of this study

1．7．The significance of this study

References

Chapter Ⅱ：Polymersome Nanoreactors with Tumor pH-Triggered Selective Membrane Permeability for Prodrug Delivery，Activation，and Combined Oxidation-Chemotherapy

2．1． Introduction

2．2． Materials and methods

2．2．1．Materials

2．2．2．Characterization

2．2．4．Critical aggregation concentration of Bz-MPE Polymersomes

2．2．5．Determination of Protonation Degree of PEG114-b-P(BzMA126-co-MPE39) Polymersomes

2．2．6．pH-triggered membrane permeability of Bz-MPE Polymersomes

2．2．8．Fluorophore loaded polymersomes preparation (DiR@Bz-MPE)

2．2．9．Synthesis of PEG114-b-P(BzMAx-co-MPEy)n amphiphilic block copolymers

2．2．10．Synthesis of phenylboronic pinacol ester-caged CPT prodrugs

2．2．11．Synthesis of Phenylboronic Pinacol Ester-Caged PTX(ProPTX)

2．2．12．Preparation of GOD and prodrug-loading nanoreactors

2．2．13．Molecular weight-selective membrane permeability

2．2．14．Quantification of H2O2 production

2．2．15．Drug release profiles

2．2．16．In vitro cytotoxicity

2．2．17．Intratumorally E2O2 level detection

2．2．18．In vivo ProCPT activation in liver and tumor evaluation

2．2．19．Antitumor efficacy and systemic toxicity

2．2．20．Statistical analysis

2．3． Results

2．3．1．Synthesis of block copolymers and prodrugs for preparation of polymersome nanoreactors

2．3．2．Tunable selective membrane permeability

2．3．3．Polymersome nanoreactor preparation and characterization

2．3．4．In vitro cytotoxicity

2．3．5．In vivo pharmacokinetics and biodistribution

2．3．6．Antitumor efficacy

2．4．Discussion

2．5．Conclusions

References

Chapter Ⅲ：Cisplatin Resistance Reversal of Lung Cancers by Tumor Acidity Activable Vesicular Nanoreactors via Tumor Oxidative Stress Amplification

3．1．Introduction

3．2． Materials and Methods

3．2．1．Materials

3．2．2．Synthesis of FITC or Cypate-labelled Glucose Oxidase(FITC-GOD and Cypate-GOD)

3．2．3．Synthesis of PEG-b-P(BzMA-co-PEMA) Block Copolymet

3．2．4．Preparation of Cisplatin and GOD Co-loaded Polymeric Nanoreactors

3．2．5．pH-Triggered Membrane Permeability Analyses

3．2．6．H2O2 Production and Cisplatin Release

3．2．7．Cytotoxicity Evaluation

3．2．8．Cellular Uptake of Platinum and DNA Platination

3．2．9．Caspase 3 Activity Evaluation

3．2．10．In Vitro Intracellular ROS，Caspase 3 Activity and Apoptosis Rate Evaluation

3．2．11．In Vivo Biodistribution and Intratumor ROS Level Evaluation

3．2．12．In Vivo Antimmor Activity

3．2．13．Statistical Analysis

3．3．Results and Discussion

3．3．1．Preparation of Polymeric Nanoreactors

3．3．2．Cytotoxicity Evaluation

3．3．3．Pt Cellular Uptake and Pt-DNA Adduet

3．3．4．In Vitro ROS，Caspase 3 Activity and Apoptosis

3．3．5．In Vivo Antitumor Efficacy against Cisplatin-Resistant Lung Tumor

3．4．Conclusion

Reference

Chapter Ⅳ：Mitochondria Targeting Polymet Prodrug Nanoparticles to Overcome Multi-Drug Resistance Through Orchestrated Mitochondrial Oxidative Stress Amplification and DNA Damage

4．1． Introduction

4．2． Material and Methods

4．2．1．Materials

4．2．2．Instrumentation

4．2．3．Compound 1 Synthesis

4．2．4．Synthesis of Thioketal Linker(TK)

4．2．5．Compound 2 Synthesis

4．2．6．Compound 3 Synthesis

4．2．7．DOX Monomer Synthesis

4．2．8．Synthesis of Cinnamaldehyde Derivative

4．2．9． Synthesis of Cinnamaldehyde Monomer(CNM)

4．2．10．Synthesis of FA-Aikyne

4．2．11．Synthesis of N3-PEOGMA

4．2．12．Determination of Critical Micelle Concentration(CMC)

4．2．13．Synthesis of N3-PEOGMAm-b-P(CNMx-co-DOXy) Polymer

4．2．14．Synthesis of TPP or FA-terminated-PEOGMAm-b-P(CNMx-co-DOXy) Polymers

4．2．15．Self-Assembly and Nanoparticle Stability Evaluation

4．2．16．DOX Rdease Evaluation

4．2．17．Cell Viability and Live／Dead Assays

4．2．18．Mitochondria Drug-Targeting Localization

4．2．20．In Vivo Antitumor Activity and Histological Analysis

4．2．21．Statistical analysis

4．3． Results and Discussion

4．3．1．Synthesis and Characterization of Monomers and Polymers

4．3．2．Nanoparticle Preparation，Stability and Drug Release Studies

4．3．3．Cell viability and Live and Dead evaluation results

4．3．4．Mitochondria Targeting Localization

4．3．5．Intracellular ROS level evalnation results

4．3．6．Antitumor Efficacy

4．4．Conclusion

Reference

Chapter Ⅴ：General Conclusion and Future Perspectives

5．1．General conclusion

5．2．Future outlooks

Acknowledgements

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