癌癥治療中納米反應(yīng)器的應(yīng)用和克服腫瘤多藥耐藥性的新策略
發(fā)布時間：2021-01-17 13:50
癌癥這種疾病在人類中持續(xù)且劇烈地增長。跟以往相比,目前更加需要高超的治療策略來實現(xiàn)有效的治療。本論文的題目為“癌癥治療中納米反應(yīng)器的應(yīng)用和克服腫瘤多藥耐藥性的新策略”。論文由四章組成,并都基于個人的相關(guān)工作。論文側(cè)重于癌癥治療性納米反應(yīng)器的設(shè)計和逆轉(zhuǎn)腫瘤耐藥性新策略的開發(fā)。以下是各章節(jié)工作的摘要:第一章癌癥作為人類日益嚴重的健康問題,在導(dǎo)致全球每年重大死亡的嚴重疾病中排名第二。盡管化學(xué)療法是大多數(shù)癌癥的主要治療選擇,但由于多藥耐藥性和嚴重的副作用,其在臨床上的應(yīng)用受到嚴重限制。在已報道的增強的癌癥治療效果的同時減輕副作用的各種方法中,可包被外源性治療酶的納米反應(yīng)器的應(yīng)用是一種非常有前途的癌癥治療策略。盡管如此,仍需要進一步的努力來克服領(lǐng)域中的一些阻礙,例如復(fù)雜的制備工序,納米反應(yīng)器固有的膜滲透性,脫靶,應(yīng)用治療性納米反應(yīng)器所需的多個步驟等等。在本章中,我們著重介紹了用于癌癥治療和診斷的治療性納米反應(yīng)器的當(dāng)前進展和局限性,其中包括一些非常新穎的治療方法和納米反應(yīng)器在開發(fā)過程中的阻礙。此外,我們提出了兩種新型治療策略來克服常規(guī)化學(xué)療法中經(jīng)常遇到的多藥耐藥性�？傮w而言,本論文的研究有望為現(xiàn)下...
【文章來源】：中國科學(xué)技術(shù)大學(xué)安徽省 211工程院校 985工程院校
【文章頁數(shù)】：212 頁
【學(xué)位級別】：博士
【文章目錄】：
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
本文編號：2983006
【文章來源】：中國科學(xué)技術(shù)大學(xué)安徽省 211工程院校 985工程院校
【文章頁數(shù)】：212 頁
【學(xué)位級別】：博士
【文章目錄】：
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
本文編號：2983006
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