脂质体多聚物混合型纳米颗粒携带FOLFIRINOX有效成分治疗胰腺癌的疗效研究

Pancreatic cancer is one of the most difficult cancer to treat,and the 5 year survival rate is 3%. 5-Fluorouracil/Leucovorin combined with Irinotecan and Oxaliplatin (FOLFIRINOX) have been made a breakthrough in the treatment of pancreatic cancer. But the application of this regimen has been limited because of severe side effect. In recent years, nanoparticles-modified chemotherapeutic reagents have demonstrated excellent efficacy in patients with pancreatic cancer such as nab-paclitaxel. In this study, we designed a novel amphiphilic copolymer vehicle (mPEG-PLGA) covered with liposomes, and then optimized the target effect of the vehicle by PEG and RGD. With this vehicles, we carried the effective components of the FOLFIRINOX to decrease the toxicity and increase the efficacy. Furthermore, we have constructed a pancreatic tumor tissue derived xenograft animal model to evaluate the safety and efficacy, thus providing new strategies for the treatment of pancreatic cancer.

胰腺癌是最难治的恶性肿瘤之一，五年生存率仅3%。胰腺癌对传统放化疗治疗反应极差，联合化疗FOLFIRINOX方案（5-氟尿嘧啶/亚叶酸钙、奥沙利铂、伊利替康）在胰腺癌治疗上取得了突破性进展，然而该疗法由于存在严重的副反应，特别是在中国人群中限制了其临床应用范围。近年纳米修饰的化疗药物(如白蛋白紫衫醇)在胰腺癌治疗领域取得了突破性进展，我们拟设计双亲性聚合物纳米颗粒外包脂质体集成各种优秀性能，制备混合型药物载体，并通过聚乙二醇（PEG）和精氨酸-苷氨酸-天冬氨酸（RGD）修饰优化其靶向性，包载FOLFIRINOX有效成分减少其毒性并增强药效，进一步利用临床组织标本构建的胰腺癌原位模型，评估其安全性和有效性，进而通过这种脂质体多聚物混合型载体为提高胰腺癌的疗效提供新的治疗策略。

2011年发表在新英格兰医学杂志上的FOLFIRINOX方案是胰腺癌治疗领域的代表性成果，但该方案存在着严重的不良反应。本研究根据FOLFIRINOX方案中药物的化学性质，采用一种多层磷脂-聚合物混合型纳米载体，实现了三种有效治疗成分（5氟尿嘧啶，伊立替康，奥沙利铂）的分层包载。该纳米载体在体内能明显提高药物在体内循环中的半衰期，同时由于被动靶向效应和纳米载体表面修饰有RGD多肽，肿瘤靶向性进一步提高。在小鼠移植瘤试验中，传统的FOLFIRINOX方案仅仅使肿瘤缩小了30%左右，而该新型纳米药物的肿瘤治疗效果明显增强，肿瘤的体积缩小了近80%。更重要的是，由于药物的肿瘤靶向性提高，对正常组织的损伤明显减少：注射传统FOLFIRINOX方案的小鼠出现明显的肝脏毒性和骨髓抑制，血中谷丙转氨酶和谷草转氨酶明显升高，白细胞、淋巴细胞、单核细胞、血小板明显降低，而纳米载体组的小鼠则完全正常。该研究不仅增强了药物的靶向性，且实现了化疗方案的增效减毒的药效，切实解决了临床上的治疗难题。在此基础上，我们针对吉西他滨耐药亚群开发特异性纳米载体实现基因治疗与化疗联用、包载增强免疫原性细胞死亡效应的药物加强药效、针对肿瘤细胞代谢的铁依赖性和胰腺癌乏氧微环境包载抑制剂联合抗肿瘤，为胰腺癌临床诊治和转化提供了临床前研究数据。