智能型“酶-抗癌前药”联合传输多功能介孔纳米载药系统的构建及评价

Increasingly growing numbers of researchers are paying close attention to the enzyme anticancer prodrug therapy because of the low toxicity on normal tissue in the body and the high selective cytotoxicity against cancer cells. However, the therapy has some disadvantages such as two-step treatment as well as high doses of prodrug. In the program, the anticancer prodrug of indole acetic acid was loaded into the hollow magnetic ordered mesoporous silica nanocarrier, then human serum albumin was fixed to the surface of mesoporous silicon by disulfide bonds link agents, and indole acetic acid was plugging in the carrier. Subsequently, horseradish peroxidase and tumor selective ligand of folic acid were successively linked to the surface of the human serum albumin molecule. In the treatment of cervical carcinoma, this drug delivery system get into the cervical carcinoma cells by recognition of targeting ligand folate. Disulfide linkages can be cleaved with glutathione in the cancer cell, the "valve" (human serum albumin) is subsequently opened, and the prodrugs within the nanoreservoir also are released. This prodrug will be enzymatically converted into the active drug with a higher concentration only at the tumor site. This enzyme antitumor prodrug system provided one step approach for the treatment of cancer and the controlled release of prodrug, and the positioning catalytic of enzymes for prodrug. In addition, the magnetic resonance contrast feature of the magnetic carrier also makes the detection of tumor tissue more accurate. The accomplishment of this program would give a new ideas for the fabrication of co-transmission system of enzyme prodrug.

酶-抗癌前药疗法对体内正常组织的低毒性以及对癌细胞的高选择性毒杀引起了研究者们的关注，但该疗法存在需两步治疗以及用药剂量较大等问题。本项目拟将抗癌前药吲哚乙酸装载于磁性中空有序介孔氧化硅纳米载体中，然后以二硫键分子为链接剂，将人血清白蛋白固定到介孔硅孔道口，前药吲哚乙酸便被封堵于载体中；而后在人血清白蛋白分子表面连接辣根过氧化物酶以及修饰靶向配体叶酸。以宫颈癌为治疗对象，当此载药系统通过靶向配体叶酸识别、进入宫颈癌细胞后，癌细胞内高浓度的还原型谷胱甘肽会将连接"阀门"（人血清白蛋白）的二硫键打开，而后前药吲哚乙酸便会从载体中释放出来，进而被辣根过氧化物酶氧化，在肿瘤局部产生高浓度的活性抗癌药。这就实现了酶-抗肿瘤前药体系对肿瘤的一步治疗和药物的定位控制释放，以及酶对前药的定位催化。此外，磁性载体的磁共振造影功能也使得肿瘤组织的检测更为精准。研究结果将为酶-前药联合传输体系的构建提供新思路。

虽然酶-抗肿瘤前药疗法为人们展示了广阔的应用前景，但仍有许多关键性问题亟待解决：①酶-前药疗法需要两步治疗；②第二次用药的时间也不易把握。本项目制备合成了一些列用于可同时装载前药和酶的药物控释纳米载体，通过将前药和酶同时负载在载体上从而实现酶-前药疗法的一步治疗，进而构建了一种“一步治疗且前药用量较少”的酶-抗肿瘤前药系统。其在体内传送过程中前药不释放且不被酶催化，只有当载体到达病灶部位时前药才会被可控释放，进而被前药活化酶催化为对癌细胞有杀伤作用的抗癌药。此外，在完成项目目标的前提下，利用已取得的研究成果和经验积累，进一步研究了相关生物催化剂（酶）以及人工模拟酶的催化特性，为以后深入研究新型“酶-抗肿瘤前药”提供了依据。研究结果为酶-前药联合传输体系的构建提供了新思路，为肿瘤治疗发展了新方法。