基于病毒衣壳蛋白的光可控纳米载药系统的构建及靶向抗肿瘤应用研究

Chemotherapy can destroy tumors and arrest cancer progress. Unfortunately, the treatment usually uses a series of injections of highly toxic drugs, thus the dose and frequency are limited due to severe side effects. A variety of drug delivery systems (DDS) have been studied for several decades as a potential solution to overcome the limitations of current chemotherapy.The DDS with nanoscale size can target tumor tissue more effectively than the drugs alone attributing to the enhanced permeation and retention effect. The protein shell of the tobacco mosaic virus (TMV) provides a robust and practical tubelike scaffold for the preparation of nanoscale materials.To expand the utility of TMV capsid toward the construction of DDS, in this study, two different strategies will be employed for the conjugation of new functionality to either the exterior or the interior surface of the virus. The first of these is accomplished using thiol-maleimide coupling reaction to install cisplatin, an anticancer drug, via a photo-sensitive linker in the inner cavity of capsid. Alternatively, the tyrosine residues on the capsid exterior will be modified by using a highly efficient diazonium coupling/oxime formation sequence, which installs linear poly(ethylene glycol) (PEG) chain and folic acid (FA), respectively. Through the above chemical methods, the PEGylated and FA-functionalized TMV subunits finally can be co-assembled to form an intact tubelike DDS with cisplatin installed inside. The PEGylation of the capsid exterior can be expected to prolong the blood circulation times and enhance the thermal stability. In the meantime, the attachment of FA to the exterior surface of capsid confers this DDS with high specificity toward membrane-anchored folate receptor (FR) which is overexpressed by a wide variety of human tumors. Once inside the cell, cisplatin, modified in the cavity of capsid, can be released from the DDS upon UV light irradiation, enter the nucleus and destroy selectively FR(+) tumor cells. To further demonstrate its ability to target and kill FR(+) tumor cells in vivo, the animal studies using tumor-bearing mice will be conducted by intravenous administration of this DDS.

化疗是临床上治疗肿瘤疾病的主要手段之一，但是由于化疗药物的严重毒副作用，目前已成为制约肿瘤化疗成效的主要障碍。借助于药物输送体系进行靶向治疗是一种比较有效的解决方法。纳米材料由于对肿瘤组织具有增强渗透和保留效应，因此在载药系统的构建上备受青睐。本项目以我们前期在大肠杆菌中表达纯化得到的烟草花叶病毒的衣壳蛋白为基础，构建具有肿瘤细胞靶向性、能够对外部光照应答并进行药物释放的纳米载药系统，以期克服化疗药物的毒副作用问题。采用蛋白质偶联反应对该病毒蛋白内孔的半胱氨酸进行光解离性药物分子的化学修饰，对病毒蛋白的外周导入肿瘤细胞的配体赋予该纳米药物载体靶向性，同时进行聚乙二醇链修饰以降低载体的免疫原性，增强热力学稳定性，改善药代动力学。本项目构建的具有生物相容性、高度稳定性及人工光可控制的植物病毒纳米载药系统有望在肿瘤化疗中得到实际应用。

化疗是临床上恶性肿瘤治疗的最主要的手段之一。目前化疗多使用小分子药物，存在药物在体内代谢速度快，到达肿瘤部位的有效剂量不足，对人体正常组织副作用大等问题，极大地增加了癌症病人化疗的生理及心理负担。纳米药物对实体瘤具有增强渗透和保留效应，因此能够有效提高化疗药物对肿瘤组织的靶向性并降低药物的副作用。本课题中，针对癌症化疗药物的不足之处，开展了如下的研究内容：.1）以临床应用的抗癌药物伊立替康的活性成分—7-乙基-10-羟基喜树碱（SN-38）为先导化合物，设计并合成了数十种化合物分子，并从中筛选获得5种具有不需要辅料即可在水相中自组装的小分子药物。在HT-29人结肠癌移植瘤模型中，相比伊立替康38%的抑瘤率，使用上述纳米药物抑瘤率可达78%。研究成果发表于国际著名的材料学期刊Advanced Functional Materials, 2015, 25, 4956 (影响因子11.805)。.2）以药物分子改造的技术，构建具有更高脂溶性的全新的SN-38衍生物文库，并与不同分子量的两亲性共聚高分子材料组合筛选出具有高稳定性及临床应用前景的纳米药物配方。体内外实验证明了纳米药物的抗癌效果远优于伊立替康。研究成果发表于国际顶尖化学期刊Angew. Chem. Int. Ed., 2014, 53, 11532 (影响因子11.336)。.3）针对肝癌细胞特异性核酸药物的体内输送这一难题，研发了生物相容性较高的体内siRNA输送的多肽纳米传递系统。含寡精氨酸序列的多肽通过简单的混合能够与siRNA形成稳定的纳米复合物，同时复合了肝癌细胞表面受体相结合的多肽配体。该研究成果获得专利授权一项，相关论文发表于化学Top期刊Chem. Commun., 2014, 50, 7806 (影响因子6.718)。.此外，与本基金内容相关的、以课题负责人为通讯作者的研究论文发表于Chem. Commun., 2015, 51, 6862 (影响因子6.718)，Org. Lett., 2014, 16, 4554 (影响因子6.324)与J. Org. Chem., 2014, 79, 8652 (影响因子4.638)，Int. J. Pharmaceut., 2014, 475, 60 (影响因子3.785)。并申请专利8项，其中一项获得授权。

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