生物粘附“蜘蛛网”状原位药物共递送系统应用于术后残余脑胶质瘤的治疗研究

脑胶质瘤呈浸润性生长，难以通过手术完全切除。术后残余肿瘤是引起肿瘤复发的重要因素。尽管术后联合放化疗清除残余肿瘤，治疗效果仍不尽理想。残余肿瘤区域免疫抑制状态与放化疗肿瘤杀伤效果的削弱密切相关。因此，化疗药物与免疫调节剂联用有望提高对残余肿瘤的治疗效果。申请人提出构建基于生物粘附纳米粒的“蜘蛛网”状原位药物共递送系统的治疗思路。替莫唑胺以及Na+/H+交换体抑制剂卡立泊来德分别作为化疗药物和免疫调节剂应用于递送系统中。通过聚乳酸-超支化聚甘油醚包封上述两种药物制备成纳米粒，将超支化聚甘油醚表面羟基氧化成醛基，转化为生物粘附纳米粒，喷涂于残余肿瘤表面，生物粘附纳米粒表面醛基可以与细胞膜蛋白氨基形成共价连接。为了进一步增加载药纳米粒滞留，采用双末端氨基聚乙二醇二次喷涂，在残余肿瘤区域建立“蜘蛛网”状原位药物共递送系统。该系统能够长效贴合肿瘤区域，释放化疗药物和免疫调节剂，进而发挥协同治疗作用。

In clinical practice, it is difficult to remove gliomas completely by surgery because of their infiltrative growth pattern. The existence of residual tumor is the leading cause of tumor reoccurrence and poor prognosis after glioma resection. Even though followed by chemotherapy or radiotherapy, the overall treatment effects are not satisfying. It is highly relevant that the immunosuppression status in residual gliomas diminishes the tumor killing effects of chemotherapy or radiotherapy. The promise of combination use of chemo-drugs and immunosuppression inhibitors is encouraging for treatment of residual glioma. Herein, we have proposed a “spider-web” like in-situ drug co-delivery system based on bioadhesive nanoparticles（BNPs）for treating residual gliomas. Temozolomide (TMZ) and a Na+/H+ exchange inhibitor cariporide (CP) are selected as chemo-drug and immunosuppression inhibitor, respectively. Both drugs are encapsulated into polylactic acid-hyperbranched polyglycerol (PLA-HPG) nanoparticles. The drug loaded nanoparticles are converted into bioadhesive nanoparticles (BNPs) by generating an aldehyde-rich corona through NaIO4 oxidation. After spraying onto the surface of residual glioma, the aldehydes on the BNPs readily form a variety of linkages with amino groups on membrane proteins via Schiff-base bonds. To enhance the retention of BNPs, NH2-PEG-NH2 is further sprayed onto the BNPs layer, forming a “spider-web” like in-situ drug co-delivery system at the residual glioma site. The in-situ drug co-delivery system could closely attach to the residual gliomas through covalent conjugation and process a prolonged retention and sustained drug release profile. Furthermore, the in-situ drug co-delivery system would exhibit a synergetic therapeutic effect at the residual glioma site.