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类型 基础研究 预答辩日期 2018-05-09
开始(开题)日期 2016-09-05 论文结束日期 2018-03-14
地点 化工楼319 论文选题来源 国家自然科学基金项目     论文字数 6 (万字)
题目 功能化铂类纳米药物设计及抗肿瘤活性评价
主题词 铂类药物,靶向运输,智能释放, 纳米药物, 近红外光
摘要 铂类抗肿瘤药物具有优良的抗肿瘤活性,在癌症治疗方面有着举足轻重的地位,但是水溶性差、严重的毒副作用及耐药性等缺点限制了其在临床上的进一步推广。随着人们对社会医疗水平要求的提高,铂类抗肿瘤药物存在的缺点被不断放大,寻找新的途径去缓解甚至克服这些弊端是研究学者一直在孜孜不倦地探究的问题。 纳米技术致力于设计、合成及表征功能化纳米材料,在药物运输方面的应用被广泛期待改变癌症治疗和生物技术产业的格局。作为一个功能化的复合药物,纳米药物具有稳定性好、毒副作用小、生物利用度高等许多突出的优点,显示出了广阔的应用前景。然而,纳米药物在一定程度上克服了传统抗肿瘤药物水溶性差、毒副作用大及耐药性等重大问题,但是想要替代传统抗肿瘤治疗的化疗方案,成为应用于临床的首选药物仍然面临很多需要改善的问题。基于以上的总结思考,本论文主要从以下两个方面开展工作:(1)研究促进药物运输的不同靶向策略;(2)研究控制药物释放的不同智能释放策略。通过从这两个重点方面进行研究,以期设计制备性能最佳的智能纳米载药系统,达到最好的抗肿瘤治疗效果。 在靶向配体介导的药物载体定向运输方面,我们选用了叶酸、cRGD、曲妥珠单抗为靶向配体偶联到纳米载体的表面。和没有偶联靶向配体的纳米载体相比,在考察的几个肿瘤细胞(胃癌细胞:SGC-7901, MGC-803;乳腺癌细胞:MCF-7,MDA-MB-231,SK-BR-3)中靶向纳米载体都表现出了不同程度的靶向作用效果,尤其是偶联曲妥珠单抗以后的药物载体,被乳腺癌细胞SK-BR-3摄取的效率大大提高。另外,我们还通过偶联全反式维甲酸(RA)和三苯基膦(TPP)设计了两个次级靶向药物前体分子,实验结果也显示RA和TPP能够将顺铂和雷公藤红素分别靶向亚细胞器细胞核和线粒体,从而表现出更高效的治疗效果。 在设计药物的刺激-响应释放方面,我们在设计的纳米系统中引入了pH、近红外光及氧化还原反应的单或双刺激-响应“开关”。实验结果显示,各个设计引入的刺激-响应策略都能很灵敏的实现药物的控制释放。其中,以亚胺键或二硫键为中心的核心交联纳米粒子能够显著提高在血液循环中的稳定性,当纳米粒子被肿瘤细胞摄取以后,在肿瘤细胞弱酸性或高浓度谷胱甘肽的内环境中,亚胺键或二硫键会响应断裂释放其中的药物;近红外光介导的光热转化产生的高热导致纳米载体迅速解聚,从而释放其中的药物分子。除此之外,近红外光介导的光热治疗、光动力治疗也在一定程度上大大增强了抗肿瘤治疗效果。
英文题目 DESIGN AND ANTITUMOR ACTIVITY EVALUATION OF FUNCTIONAL CISPLATINUM NANO-DRUGS
英文主题词 platinum drugs, targeted delivery, smart release, nano-drugs, near infrared light
英文摘要 Platinum-based antitumor drugs shows excellent anti-tumor activity, and has become an important role in cancer treatment. Nevertheless, the poor water solubility, serious systemic toxicities and drug resistance has limits its further promotion in clinic. With the improvement of people’s requirements for social medical treatment, the disadvantages of platinum-based antitumor drugs have been amplified, searching for new ways to alleviate or even overcome these shortcomings is the problems which scholars has been diligently explored. Nanotechnology is dedicated to the design, synthesis and characterization of functional nanomaterials, which are widely expected to change the pattern of cancer treatment and biotechnology industry. As functionalized compound drugs, nano-drugs have the advantages of good stability, low toxicity, and high bioavailability, showing a broad application prospect. However, to some extent, nano-drugs have overcome the major problems of water-solubility, toxicity and drug resistance of traditional platinum-based antitumor drugs. traditional poor water soluble antineoplastic drugs, side effects and drug resistance and other major issues, but to replace the traditional antitumor chemotherapy regimen, it is still faced with many problems that need to be improved to become the first-choice drug for clinical application. Based on the above summary thinking, this paper mainly carries on the work from the following two aspects: (1) to study different targeting strategies for drug delivery; (2) research on different intelligent release strategies for drug release. Through the study of these two key aspects, we hope to design excellent intelligent nano-carrier systems to achieve the best antitumor effect. In terms of targeted ligands mediated drug delivery, folic acid, cRGD and trastuzumab were used to conjugate the surface of the nanoparticles. Compared with the nanoparticles without targeted ligands, the targeting of nano-carriers in several selected tumor cells (Human gastric cancer cell: SGC-7901, MGC-803; Human breast cancer cell: MCF-7, MDA-MB-231, SK-BR-3) showed different levers of targeting effect. In particular, the uptake efficiency of the drug carriers on the breast cancer cell SK-BR-3 was greatly increased after been conjugated with trastuzumab. In addition, we have designed two subtargeted drug precursors by coupling all trans-retinoic acid (RA) and triphenylphosphine (TPP). The obtained experimental results also show that RA and TPP can targeted deliver cisplatin and tripterygium to the cell nucleus and mitochondria respectively, thus showing more effective therapeutic effect. In the design of the stimulus-response release of the drug, we introduced a single or dual stimulus-response "switch" of pH, near-infrared light and redox reaction in the designed nano-system. The experimental results show that the stimulus-response strategies introduced by each design can be sensitive to the control and release of drugs. Among them, the core linking nanoparticles with the imide or disulfide bonds can significantly improve the stability during the blood circulation. When the nanoparticles are internalized by tumor cells, the amines or disulfide bonds respond to the fracture release of the drug in the context of a weak acid or high concentration of glutathione in the tumor cells. Otherwise, the heat induced by near infrared light mediated photothermal conversion causes the nano-carriers to rapidly depolymerize, thus releasing the drug molecules. In addition, near infrared light mediated photothermal therapy and photodynamic therapy have greatly enhanced the anti-tumor therapeutic effect.
学术讨论
主办单位时间地点报告人报告主题
东南大学化学化工学院 2017-09-28 化工楼319 吴鸿帅 Acid-responsie polymeric doxorubicin prodrug nanoparticles encapsulating a near-infrared dye for combined photothermal-chemotherapy
东南大学化学化工学院 2017-12-30 化工楼319 游朝群 Co-delivery of cisplatin and CJM-126 via photothermal conversion nanoparticles for enhanced synergistic antitumor efficacy
东南大学化学化工学院 2015-07-23 化工楼319 施天一 cRGD/TAT dual-ligand reversibly cross-linked micelles loaded with docetaxel penetrate deeply into tumor tissue and show high antitumor efficacy in vivo
东南大学化学化工学院 2016-04-15 化工楼319 游朝群 Enhanced cytotoxicity by a benzothiazole containing cisplatin derivative in breast cells
东南大学化学化工学院 2016-08-08 化工楼319 施天一 Dual-peptide-functionalized albumin-based nanoparticles with pH-dependent self-assembly behavior for drug delivery
东南大学化学化工学院 2016-11-20 化工楼319 游朝群 Near-Infrared Light and pH Dual-Responsive Targeted Drug Carrier Based on Core-Crosslinked Polyaniline Nanoparticles for Intracellular Delivery of Cisplatin
东南大学化学化工学院 2017-04-15 化工楼319 王森林 Near infrared-assisted fenton reaction for tumor-specific and mitochondrial DNA-targeted photochemotherapy
东南大学化学化工学院 2017-07-23 化工楼319 游朝群 A strategy for photothermal conversion of polymeric nanoparticles by polyaniline for smart control of targeted drug delivery
     
学术会议
会议名称时间地点本人报告本人报告题目
第十三届全国生物无机化学学术会议 2016年10月13日-16日 上海-上海师范大学 奥曲肽纳米载药体系研究
第十届全国化学生物学学术会议 2017年9月23日-26日 武汉-华中师范大学 抗体铂药胶束偶联物的制备及其体内外活性研究
     
代表作
论文名称
Near-Infrared Light and pH Dual-Responsive Targeted Drug Carrier Based on Core-Crosslinked Polyanili
Near infrared radiated stimulus-responsive liposomes based on photothermal conversion as drug carrie
A strategy for photothermal conversion of polymeric nanoparticles by polyaniline for smart control o
Co-delivery of cisplatin and CJM-126 via photothermal conversion nanoparticles for enhanced synergis
Enhanced cytotoxicity by a benzothiazolecontaining cisplatin derivative in breast cancer cells
 
答辩委员会组成信息
姓名职称导师类别工作单位是否主席备注
王飞 正高 教授 博导 南京林业大学
朱进 正高 教授 博导 南京医科大学
孙岳明 正高 教授 博导 东南大学
周钰明 正高 教授 博导 东南大学
王明亮 正高 教授 博导 东南大学
      
答辩秘书信息
姓名职称工作单位备注
罗洋辉 其他 讲师 东南大学