量子点标记基于功能化磷脂的溶瘤病毒及其与肿瘤细胞相互作用研究

Oncolytic virus (OV) is the virus that can selectively infect and replicate in cancer cells, with minimal destruction of non-neoplastic tissue. Due to its replication, a large number of newly born virons are released on the rupture of tumor cells, and then they are able to attack other tumor cells again. Based on OV, promising methods for cancer therapy can be established. Although some OVs are in their clinic stage of development, most methods for the preparation of OV are based on the genetic engineering approach, causing the complication in operation, prone to mutation. To make things worse, there is still potential toxicity with current OV. Herein, the project is planned to develop a universal method to design and prepare OVs based on phospholipids and enveloped virus, so that the targeting of OVs and the reduction of their toxicity can be realized. First, several new types of functional phospholipids will be designed and synthesized. Second, based on the pre-established "natural fusion" approach, enveloped viruses as well as their host cells will be modified with the above-mentioned functional phospholipids. Third, the targeting of the as-prepared new OVs will be inspection and regulated with the phospholipids. Fourth, the as-prepared new OVs will be labeled with quantum dots (QDs) at the cost of losses in virus activity as less as possible. Last but not the least, based on high sensitive single particle tracking technique, the interaction between the OVs and their host cells can be investigated. The results will provide profound foundation for the structure and the function of OVs, greatly expand the application of OV in cancer therapy, and also provide the basis for individualized treatment of diseases.

溶瘤病毒是指能够特异性地侵染肿瘤细胞并在其内复制，导致肿瘤细胞死亡后释放大量子代病毒，进而再次攻击其它肿瘤细胞的一类病毒。基于溶瘤病毒可以建立新颖的癌症（恶性肿瘤）治疗方法，但目前其制备大多采用基因工程技术，操作繁琐。项目旨在基于我们前期提出的宿主细胞中功能化磷脂"自然嵌合"标记囊膜病毒新策略，建立构建溶瘤病毒的通用新方法及基于量子点单颗粒示踪技术研究溶瘤病毒与细胞相互作用的新方法。拟修饰病毒囊膜中普遍大量存在的磷脂的亲水部分来获得几类功能化磷脂，利用其在宿主细胞中标记囊膜病毒并实现病毒对肿瘤细胞的靶向识别，构建新型溶瘤病毒。在此基础上，拟采用量子点标记所构建的溶瘤病毒的非侵染决定部位，建立无损的量子点标记溶瘤病毒新方法，并基于单颗粒示踪技术研究溶瘤病毒与肿瘤细胞及相应正常细胞的相互作用。相关结果将为采用化学方法调控病毒靶向性及构建新型溶瘤病毒提供依据，为利用溶瘤病毒治疗癌症提供新的可能。

溶瘤病毒是能够特异性地感染肿瘤细胞的一类病毒。基于溶瘤病毒可以建立新型肿瘤治疗方法，但目前其制备大多采用基因工程方法，操作繁琐。项目基于我们提出的功能化磷脂在细胞膜及病毒包膜中的“自然嵌合”作用，建立了多种对包膜病毒表面修饰及靶向性调控的新策略；在开发量子点标记材料化学修饰及生物功能化新方法的基础上，建立了采用荧光亮度高、稳定性好的量子点高效温和标记病毒非侵染决定部位的新方法，有效保持了病毒的完整性及侵染能力；采用单颗粒动态示踪技术等对标记病毒与肿瘤细胞及正常细胞的相互作用进行了解析，结果表明基于功能化磷脂修饰可有效调控包膜病毒的肿瘤细胞靶向性。项目在基于功能化磷脂的病毒修饰及靶向调控、量子点标记病毒新方法方面具有显著特色并取得了突出成果。共发表SCI论文13篇，申请国家发明专利2项，其中1项获专利授权。培养了博士生3名及硕士生5名。相关结果为采用化学方法调控病毒靶向性及开发新型溶瘤病毒提供了依据，并为利用溶瘤病毒治疗癌症提供了新的可能。