【作者】 王丹；

【导师】 赵凌云；

【作者基本信息】 清华大学 ， 材料科学与工程， 2019， 硕士

【摘要】 癌症是威胁人类健康的重大疾病,临床治疗手段通常包括手术、放疗与化疗,但以上治疗策略存在疗效不佳及预后差等问题。因此,配合肿瘤临床治疗的需要,研究多功能新型复合治疗介质用于肿瘤多模态治疗,一直受到广泛关注。热疗作为一种辅助治疗模式在临床肿瘤治疗中具有很大优势,常见的热疗手段包括磁热,光热,射频以及微波消融等。为减少治疗过程对肿瘤周边正常组织产生不必要的热损伤,使热效应仅针对肿瘤组织发生作用从而提高肿瘤治疗效果,可藉由新型外场响应型热疗介质可实现此目的。在此基础上,将其他治疗或成像因子负载于热疗介质,制备功能型介质以结合诊断与多种治疗模式的综合诊疗方法是肿瘤治疗的发展趋势。因此,构建具有多种功能,能够结合诊断与治疗的复合植入材料具有广泛临床应用前景。本研究以低频电磁波下产热的新型热疗介质为核心,提出了磁性载药水凝胶作为微波增敏介质,以及基于液态金属的新型非磁性磁感应热疗介质,构建了多功能海藻酸钙微球用于成像与肿瘤联合热化疗、液态金属复合物用于肿瘤热疗和CT显影以及液态金属水凝胶作为放疗增敏介质用于乳腺癌术后综合治疗。在探究复合植入物可作为热疗介质的基础上,原创性研究镓铟合金作为药物刺激响应释放载体、肿瘤放疗增敏和CT显影示踪介质的可行性和特殊优势,针对上述介质在物性指标,生物相容性,体外肿瘤细胞毒性以及在体内荷瘤鼠肿瘤治疗的评价进行深入研究。研究结果表明海藻酸钙微球可作为一种新型高效的微波增敏介质,具有提高局部微波产热效率与改善治疗部位热分布的优势,进而使热量靶向性作用于肿瘤部位,减轻对周围组织副作用。负载抗肿瘤药物与四氧化三铁的海藻酸钙微球可实现MRI成像实时定位微球位置为热疗提供更有效指导,动物体内实验表明集微波热疗与化疗于一体的治疗模式可以有效消融肿瘤。载药液态金属复合物具有磁热、交变磁场与p H刺激响应释放和CT显影增强特性,可结合磁热疗与化疗药物有效治疗乳腺癌。凝胶剂量和细胞克隆形成实验证明液态金属作为放疗增敏介质的可行性,与自愈性水凝胶结合后制备的液态金属复合物作为一种新型的填充物,术后填充到瘤床部位实施热疗,放疗与化疗相结合的综合治疗模式,可以有效抑制肿瘤复发。更多还原

【Abstract】 Cancer is the world leading cause of death.Surgery,radiotherapy and chemotherapy are most commonly used for cancer treatment in clinical.However,due to the side effect and limited efficacy of these methods,attention has been paid on the development of novel multifunctional hybrids for tumor theranostics.As a new emerging ajuvant alternative treatment method in clinical,hyperthermia or thermotherapy have attracted enourmous interest,such as magnetic hyperthermia,photothermal theray,radiofrequency and microwave ablation.To reduce side effect to adjacent normal tissues,electromagnetic field responsive hybrids are promising to target heat into tumor site.Moreover,the development of multifunctional platform combing thermotherapy and other treatment method is proved to be effective in clinical cancer therapy.Our study is focused on the development of themal agents generating heat under low frequency electromagnetic field.Hydrogel as the microwave sensitizer and gallium based liquid metal（LM）as the magnetic hyperthermia mediator are proposed,which provide an alternative agents for microwave ablation and magnetic hyperthermia.Three multifunctional platforms,Fe₃O₄ and doxorubicin loaded uniform alginate microsperes for tumor alation,PEGylated LM hybrids for breast cancer therapy and LM hydrogel for combined postsurgical treatment were developed.Except for the study of themogeneration effect,the feasibility of LM hybrids to be applied in alternating magnetic field and p H stimuli responsive delivery,radiotherapy sensitization and CT image was also investigated.Moreover,the characterization of as prepared hybrids,biocompatibility evaluation,in vitro cytotoxicity and in vivo anti-tumor efficacy under different treatment models were systematically evaluated.The results showed that alginate microspheres fabricated by emulsification are proved to be an effective microwave sensitizer,which promoted local treatment temperature and made the heat distributed more uniformly.Combined with chemotherapy of anticancer drug,it can effectively ablate tumors.Meanwhile,due to the loading of Fe₃O₄,MRI imaging can be used to locate the microspheres,providing more effective guidance for hyperthermia.Non-magnetic gallium indium based liquid metal possessed heat generation ability under alternating magnetic field and can be used as a novel magnetic hyperthermia mediator.Drug loaded liquid metal hybrid had magnetic field and p H stimuli response release property and CT imaging enhancement characteristics.After injection into the tumor site,it can effectively treat breast cancer with the combined therapy of magnetic hyperthermia and chemotherapeutic drugs.The measurement of gel dosimetry and clonegenic assay demonstrated the feasibility of liquid metal as radiation sensitizer.Liquid metal hybrids prepared by combining with LM and self-healing hydrogel is applied for postsurgical implantation.Hyperthermia at the site of the tumor residue bed,combined with radiotherapy and chemotherapy,can effectively inhibit tumor recurrence.更多还原