可视化双靶向载dFdC金纳米微囊同步UTMD增强胰腺癌化疗效果及瞬时成像的实验研究

It has been reported that the crucial reason of insensitiveness of pancreatic cancer to chemotherapy is the rapid inactivation of the chemotherapy drug and the very low amount of drug deposition in tumor. Moreover, recent radiology technology cannot evaluate chemotherapy effect in time. In our previous study, it has been found that nano particles prepared by PLGA/PEG material can increase the bioactivity of easily degraded chemotherapy drug and improve its long term systemic circulation, in addition, Ultrasound Targeted Microbubble Destruction (UTMD) technology could enhance the delivery of nano particles. However, resolving the the difficulties of modulating target drug depositon and innovating corresponding imaging technology to instantaneously visualize the therapy effect are in urgent need. This study will be carried on first by preparing the PLGA/PEG-Gold nano capsule, in which wrapped with easily degraded gemcitabine, and on surface of which modified with specific antibody CA19-9 and CEA. Secondly, This multifunctional carrier will consquently be propelled by UTMD in order to increase the drug intake. Meanwhile, the acoustic scattering characteristic of gold nano particles on carrier surface will be used to real time imaging under ultrasound. The purpose of this study is to establish a new mode of adjuvant therapy in pancreatic cancer, which integrates not only effective and safe cell targeted chemotherapy but a new real time cell target imaging method.

药物快速代谢及无法高浓度聚集肿瘤组织是长期以来胰腺癌化疗耐受的关键原因；现有的各种影像学手段又无法及时评价治疗疗效。课题组前期利用PLGA/PEG材料制备荷药载体，提高了易降解药物的生物利用率并能促进药物在体内长效循环；利用超声靶向破坏微泡（UTMD）技术增强了载药纳米粒在局部组织的摄取。但靶向性调控药物释放和浓集及瞬时"可视化"特异成像评价胰腺癌治疗疗效是亟需解决的两大技术难题。本课题拟制备PLGA/PEG新型金纳米微囊，将其内部包裹易降解的吉西他滨(dFdC)，表面修饰特异识别胰腺癌细胞的CA19-9及CEA抗体；在UTMD"助推"下荷药载体特异性大量进入胰腺癌细胞；同时利用载体表面纳米金颗粒的表面效应和声学散射特性进行分子靶向超声造影成像，以期实现提高胰腺癌化疗疗效的同时，及时进行分子靶向超声造影成像评估胰腺癌的治疗疗效，从而为胰腺癌建立一项安全有效的一体化分子靶向辅助治疗新手段。

胰腺癌化疗的瓶颈是容易产生化疗耐受以及化疗药物带来的全身副反应。mPEG-PLGA-PLL纳米微囊是一种优良的缓释载体，且可以通过表面修饰靶向分子实现靶向递药；课题组前期已证实超声靶向破坏微泡技术（UTMD）是定向增强药物递送的安全有效手段。本课题将mPEG-PLGA-PLL纳米微囊表面修饰抗CA19-9抗体，内部包载紫杉醇，能够显著增强胰腺癌细胞以及荷瘤裸鼠肿瘤模型对紫杉醇的摄取；特别是在UTMD的辅助下，摄取快速达峰且峰值明显提高，极大的增强了紫杉醇的化疗效果，肿瘤生长抑制率明显提高，凋亡比例升高，生存期延长，且无明显毒副作用；进一步的药代动力学证实了mPEG-PLGA-PLL纳米微囊良好的抗代谢的功能，延长了紫杉醇代谢的半衰期，减缓了清除率，靶向纳米包载的紫杉醇以及UTMD将更多的药物集中在肿瘤部位，从而减少了紫杉醇在内脏器官的蓄积，因此明显减轻了副反应，改善了肝肾功能。此外，在胰腺癌裸鼠模型中观察到，纳米微囊的超声造影效果甚至可以比拟声诺维，是一种良好的增强超声对比效果的造影剂。因此，靶向载紫杉醇的mPEG-PLGA-PLL纳米微囊联合UTMD提供了一种胰腺癌一体化诊疗的新模式。项目研究成果在Theranostics、Oncotarget等国内外期刊发表。