癌症诊治用多功能复合脂质体的可控自组装

Chemotherapeutic drugs can enhance the efficiency of photodynamic therapy greatly, so chemotherapy combined with photodynamic therapy becomes a hot topic. Unlike chemotherapeutic drugs, photosensitizers do not need release during photodynamic therapy. Thus, it is a big challenge to use one naocarrier to co-deliver both chemotherapeutic drug and photosensitizer for chemotherapy combined with photodynamic therapy. Herein, the applicant synthesizes a new type of hybrid lipid by covalent attachment of porphyrin. Then, a nanohybrid liposome is fabricated from such hybrid lipid by self-assembly process for the encapsulation of doxorubicin. The porphyrins conjugated to the lipid bilayer of hybrid liposomes act as photosensitizer for photodynamic diagnosis and therapy without any leaking. Doxorubicin loaded in such liposomes can be used for chemotherapy. In addition, its release rate can be controlled by adjusting self-assembly process and Si-O-Si density of liposomes. Many hydroxyl groups exist on the surface of hybrid liposomes, making them more hydrophilic and dispersible in water. Folic acid can be attached onto the surface of liposomes by the reaction between folic acid and hydroxyl groups so the hybrid liposomes can be targetedly delivered to the tumor. Thus, we can construct multifunctional nanohybrid liposomes which integrate different functions including targeting, controlled release, fluorescent diagnosis, photodynamic therapy and chemotherapy.

化疗药物能显著增强光动力疗效，所以将光动力疗法与化疗联合已成为当前的研究热点。与化疗药物不同，光敏剂不需要释放。因此，如何用同一种纳米药物载体负载化疗药物和光敏剂对癌症进行化疗和光动力治疗是医药界面临的一个很大的挑战。申请人拟在已有基础上通过共价键将卟啉与脂质分子连接，合成含卟啉的复合脂质，并以此为自组装基元制备含卟啉的复合脂质体包埋阿霉素。一方面，脂质双层中以共价键连接的卟啉用于光动力荧光诊断与治疗，解决光敏剂泄漏的问题。另一方面，脂质体中包埋的阿霉素用于化疗，并通过调控脂质的自组装和Si-O-Si表面缩合度控制阿霉素的释放速度。脂质体表面存在的硅羟基使其具有很好的水分散性。通过硅羟基将叶酸等靶向分子连接到脂质体上，利用叶酸与叶酸受体间的特异性亲合力，使复合脂质体能有效地靶向定位于肿瘤组织部位。这样，可得到集靶向、药物控释、荧光诊断、光动力治疗与化疗于一体的多功能纳米复合脂质体。

通过多步反应合成了6个不同结构的复合脂质化合物，并以此为组装基元制备了复合脂质体，分别用于包埋亲水性抗癌药物阿霉素和疏水性抗癌药物紫杉醇。研究发现，在复合脂质体中掺入一定比例的磷脂，可以控制药物的释放速度。利用复合脂质体同时包埋氧化铁纳米粒子和阿霉素制备了磁性阿霉素复合脂质体。在外加磁场作用下，这种脂质体纳米粒子的细胞摄取率和对肿瘤细胞的杀伤力显著增强。以共价键连接的卟啉复合脂质为自组装基元制备了含卟啉的复合脂质体，并以此为载体包埋阿霉素。一方面，脂质双层中以共价键连接的卟啉用于光动力荧光诊断与治疗，解决了光敏剂泄漏的问题。另一方面，脂质体中包埋的阿霉素用于化疗，并通过调控复合脂质体中Si-O-Si表面缩合度控制阿霉素的释放速度。这样，可得到集靶向、药物控释、荧光诊断、光动力治疗与化疗于一体的多功能纳米复合脂质体。以复合脂质、磷脂和两亲性荧光染料作为自组装基元，通过声振空化法制备了超声/荧光双模态微泡超声造影剂，使人们只需使用一种造影剂就能实现荧光和超声两种功能的成像，从而结合了荧光成像灵敏度高和超声成像分辨率高的优点。.迄今为止，在《Theranostics》、《Acs Nano》和《Biomaterials》等SCI期刊上发表标注该项目资助的论文36篇。申请发明专利8项。作为第一完成人获省部级自然科学一等奖1项（2014年）。.人才培养：已毕业博士4名，硕士3名。其中1人获得教育部博士生学术新人奖，2人获得研究生国家奖学金。.在ASME 5th NanoEngineering for Medicine and Biology Conference、IEEE-NANOMED 2015 conference等国内外学术会议上做邀请报告。.分别邀请了日本奈良先端科技大学的菊池纯一教授、麻省大学Vincent M. Rotello教授和佐治亚理工大学的包刚教授等国内外著名学者来我校交流合作或讲学。