MAI/H2O2/NIR三重应答脂质体改善“缺氧”肿瘤的PDT效果的研究

Photodynamic therapy (PDT) for the tumor treatment depends on reactive oxygen species (ROS) generated from oxygen to kill cancer cells. The oxygen-dependent is the most important characteristic of PDT. However, the low effect caused by hypoxic tumors and poor targeting ability greatly limit its effectiveness. In this project, the hydrophilic CAT and the lipophilic photosensitizer Ce6 are designed to encapsuled into the cavum and the lipid bilayers of the liposomes, respectively. Moreover, the mitochondria targeting group triphenylphosphonium (TPP) is conjugated on the surface of the liposomes. The mitochondrial active identification (MAI)/H2O2 response/ NIR photo-response triple responsive liposomes are designed as the carrier. There are three advantages for this carrier: (1) The co-encapsulation of CAT and Ce6, which not only improve the stability of Ce6, but also decompose H2O2 which is highly produced in tumors into O2, improving the hypoxic situation in tumor site and enhancing the effectiveness of PDT; (2) The mitochondria targeting carrier of PDT could be formed by conjugation of mitochondria targeting group TPP on the surface of the liposomes based on metabolic variation in tumor cells. Thus, this carrier will improve the delivery efficiency and PDT effectiveness by tumor active targeting ability; (3) The byproducts of this system are water and O2, which are harmless to the human body. Therefore, this system can be combined with medication and photothermal therapy, exhibiting potential in a wide range of applications.

针对肿瘤的光动力治疗需要激发氧分子生成活性氧簇引发细胞凋亡，O2依赖性是其重要特征。然而在其应用中存在肿瘤缺氧状态造成的疗效低下及靶向性差的问题，极大程度地限制了PDT的疗效。本课题拟将水溶性过氧化氢酶（CAT）包载于内水腔中，将脂溶性光敏剂Ce6包载于双分子层中，并在脂质体表面键合线粒体靶向基团三苯基膦 (TPP)，设计线粒体主动识别(MAI)/H2O2响应/近红外光响应的三重应答脂质体。该载体具有以下优点：（1）CAT与Ce6共同包载，不仅提高Ce6的稳定性，并且CAT可分解在肿瘤部位大量产生的H2O2提供O2，改善肿瘤的缺氧状态，提高PDT治疗效果；（2）将线粒体靶向基团TPP键合于脂质体表面，构建基于肿瘤细胞内代谢变异的线粒体靶向载体，使其具有肿瘤主动靶向性，提高光敏剂递送效率和治疗效果；（3）此体系副产物为无毒的水和O2，可结合药物、光热治疗等领域，具有广泛应用价值。

光动力疗法由光敏剂在光激活产生下的单线态氧（1O2）来杀死癌细胞，而光动力的治疗效果依赖于光敏剂在肿瘤部位的滞留，因此，将光敏剂传递给亚细胞细胞器以提高治疗效率具有重要意义。本研究旨在构建一种具有线粒体靶向功能的递送系统，选用脂质体作为光敏药物的运输载体，通过共价连接在表面修饰上线粒体靶向基团三苯基溴化磷(TPP)，使其将光敏药物定向运送到线粒体内；并通过荧光共振能量转移的方式实现光敏剂激活状态的可控性。此外，考虑到在光动力治疗过程中，氧气消耗和实体瘤中固有的缺氧微环境可能进一步导致供氧不足，阻碍治疗效果，我们将含氧饱和的全氟己烷与空心纳米材料组合，并在其表面负载光敏剂，以改善肿瘤乏氧，增强的光动力疗效。重点研究了体系的构建过程、稳定性，在细胞实验中评估增强的细胞毒性和线粒体靶向性，通过活体实验研究了光敏剂在肿瘤处增强的抗肿瘤治疗效果、改善肿瘤乏氧情况，为推动光动力治疗提供了重要的实验依据。

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