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
发布时间：2021-01-17 13:50
癌症这种疾病在人类中持续且剧烈地增长。跟以往相比,目前更加需要高超的治疗策略来实现有效的治疗。本论文的题目为“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”。论文由四章组成,并都基于个人的相关工作。论文侧重于癌症治疗性纳米反应器的设计和逆转肿瘤耐药性新策略的开发。以下是各章节工作的摘要:第一章癌症作为人类日益严重的健康问题,在导致全球每年重大死亡的严重疾病中排名第二。尽管化学疗法是大多数癌症的主要治疗选择,但由于多药耐药性和严重的副作用,其在临床上的应用受到严重限制。在已报道的增强的癌症治疗效果的同时减轻副作用的各种方法中,可包被外源性治疗酶的纳米反应器的应用是一种非常有前途的癌症治疗策略。尽管如此,仍需要进一步的努力来克服领域中的一些阻碍,例如复杂的制备工序,纳米反应器固有的膜渗透性,脱靶,应用治疗性纳米反应器所需的多个步骤等等。在本章中,我们着重介绍了用于癌症治疗和诊断的治疗性纳米反应器的当前进展和局限性,其中包括一些非常新颖的治疗方法和纳米反应器在开发过程中的阻碍。此外,我们提出了两种新型治疗策略来克服常规化学疗法中经常遇到的多药耐药性。总体而言,本论文的研究有望为现下...
【文章来源】：中国科学技术大学安徽省 211工程院校 985工程院校
【文章页数】：212 页
【学位级别】：博士
【文章目录】：
摘要
Abstract
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
1.8 References
Chapter Ⅱ Polymersome Nanoreactors with Tumor pH-Triggered SelectiveMembrane 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
2.2.3 Synthesis of FITC Conjugates
2.2.4 Critical aggregation concentration of Bz-MPE Polymersomes
114-b-P(BzMA126-co-MPE39)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
2.2.7 In Vitro Observation of Live/Dead Cells after Different Treatments
2.2.8 Fluorophore loaded polymersomes preparation （DiR@Bz-MPE）
114-b-P（BzMAx-co-MPEy）n amphiphilic blockcopolymers"> 2.2.9 Synthesis of PEG114-b-P（BzMAx-co-MPEy）n amphiphilic blockcopolymers
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
2O2 production"> 2.2.14 Quantification of H2O2 production
2.2.15 Drug release profiles
2.2.16 In vitro cytotoxicity
2O2 level detection"> 2.2.17 Intratumorally H2O2 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 ofpolymersome 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 parmacokinetics and biodistribution
2.3.6 Antitumor efficacy
2.4 Discussion
2.5 Conclusions
2.6 References
Chapter Ⅲ Cisplatin Resistance Reversal of Lung Cancers by Tumor AcidityActivable 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 andCypate-GOD）
3.2.3 Synthesis of PEG-b-P（BzMA-co-PEMA） Block Copolymer
3.2.4 Preparation of Cisplatin and GOD Co-loaded Polymeric Nanoreactors
3.2.5 pH-Triggered Membrane Permeability Analyses
2O2 Production and Cisplatin Release"> 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 RateEvaluation
3.2.11 In Vivo Biodistribution and Intratumor ROS Level Evaluation
3.2.12 In Vivo Antitumor 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 Adduct
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
3.5 Reference
Chapter Ⅳ Mitochondria Targeting Polymer Prodrug Nanoparticles to OvercomeMulti-Drug Resistance Through Orchestrated Mitochondrial Oxidative StressAmplification 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-Alkyne
3-PEOGMA"> 4.2.11 Synthesis of N3-PEOGMA
4.2.12 Determination of Critical Micelle Concentration （CMC）
3-PEOGMAm-b-P（CNMx-co-DOXy） Polymer"> 4.2.13 Synthesis of N3-PEOGMAm-b-P（CNMx-co-DOXy） Polymer
m-b-P（CNMx-co-DOXy）Polymers"> 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 Release Evaluation
4.2.17 Cell Viability and Live/Dead Assays
4.2.18 Mitochondria Drug-Targeting Localization
4.2.19 In Vitro Intracellular ROS Evaluation
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 evaluation results
4.3.6 Antitumor Efficacy
4.4 Conclusion
4.5 Reference
Chapter Ⅴ General Conclusion and Future Perspectives
5.1 General conclusion
5.2 Future outlooks
Acknowledgements
List of Publications
本文编号：2983006
【文章来源】：中国科学技术大学安徽省 211工程院校 985工程院校
【文章页数】：212 页
【学位级别】：博士
【文章目录】：
摘要
Abstract
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
1.8 References
Chapter Ⅱ Polymersome Nanoreactors with Tumor pH-Triggered SelectiveMembrane 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
2.2.3 Synthesis of FITC Conjugates
2.2.4 Critical aggregation concentration of Bz-MPE Polymersomes
114-b-P(BzMA126-co-MPE39)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
2.2.7 In Vitro Observation of Live/Dead Cells after Different Treatments
2.2.8 Fluorophore loaded polymersomes preparation （DiR@Bz-MPE）
114-b-P（BzMAx-co-MPEy）n amphiphilic blockcopolymers"> 2.2.9 Synthesis of PEG114-b-P（BzMAx-co-MPEy）n amphiphilic blockcopolymers
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
2O2 production"> 2.2.14 Quantification of H2O2 production
2.2.15 Drug release profiles
2.2.16 In vitro cytotoxicity
2O2 level detection"> 2.2.17 Intratumorally H2O2 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 ofpolymersome 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 parmacokinetics and biodistribution
2.3.6 Antitumor efficacy
2.4 Discussion
2.5 Conclusions
2.6 References
Chapter Ⅲ Cisplatin Resistance Reversal of Lung Cancers by Tumor AcidityActivable 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 andCypate-GOD）
3.2.3 Synthesis of PEG-b-P（BzMA-co-PEMA） Block Copolymer
3.2.4 Preparation of Cisplatin and GOD Co-loaded Polymeric Nanoreactors
3.2.5 pH-Triggered Membrane Permeability Analyses
2O2 Production and Cisplatin Release"> 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 RateEvaluation
3.2.11 In Vivo Biodistribution and Intratumor ROS Level Evaluation
3.2.12 In Vivo Antitumor 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 Adduct
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
3.5 Reference
Chapter Ⅳ Mitochondria Targeting Polymer Prodrug Nanoparticles to OvercomeMulti-Drug Resistance Through Orchestrated Mitochondrial Oxidative StressAmplification 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-Alkyne
3-PEOGMA"> 4.2.11 Synthesis of N3-PEOGMA
4.2.12 Determination of Critical Micelle Concentration （CMC）
3-PEOGMAm-b-P（CNMx-co-DOXy） Polymer"> 4.2.13 Synthesis of N3-PEOGMAm-b-P（CNMx-co-DOXy） Polymer
m-b-P（CNMx-co-DOXy）Polymers"> 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 Release Evaluation
4.2.17 Cell Viability and Live/Dead Assays
4.2.18 Mitochondria Drug-Targeting Localization
4.2.19 In Vitro Intracellular ROS Evaluation
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 evaluation results
4.3.6 Antitumor Efficacy
4.4 Conclusion
4.5 Reference
Chapter Ⅴ General Conclusion and Future Perspectives
5.1 General conclusion
5.2 Future outlooks
Acknowledgements
List of Publications
本文编号：2983006
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