ATF多肽介导、共载USPIO/5-氟尿嘧啶的多功能脂质体对原位胰腺癌的诊疗一体化实验研究

Insufficient contrast-enhanced MR imaging and poor sensitivity with chemical drug to pancreatic cancer are two major problems in its clinical diagnosis and treatment, which always resulting in the patients’s management failure. Our previous report proved: an immunoliposome co-delivered with contrast agent USPIO and doxorubicin(DOX) possessed targeted diagnose and therapy effect on pancreatic tumor xenograft mouse model. However, in the clinical treatment of orthotopic pancreatic cancer often faces with much more difficulties, such as covert physiological position and complex micro environment. Therefore, therapeutic agent with prominent specifically targeting and instant drug release ability is urgently needed to further improve the treatment of pancreatic cancer. The preliminary experiment verified: 10 nm USPIO can not only enhance the MRI contrast sensitivity, but also produce magneto-caloric effect by the RF magnetic field, leading its thermo-sensitive carrier to deform instantly and release drug. In addition, recent studies have shown that ATF polypeptide has marked targeting and strong penetration ability to urokinase type plasminogen activator receptors which overexpression on pancreatic tumor and tumor stromal. Thus, the aim of this study is to construct an ATF-mediated multifunctional liposome co-delivering USPIO and 5-fluorouracil, referred to ATF-(USPIO/5Fu)-Lip, which could achieve the diagnosis and therapy for pancreatic cancer. Research would provide a new way for the integrated therapy on pancreatic cancer.

影像对比度低、化药敏感性差是胰腺癌临床诊疗的两大难题，常致患者贻误诊断与治疗时机。课题组前期报道过共载MR对比剂USPIO和化药阿霉素的胰腺癌靶向脂质体，该脂质体成功地实现了小鼠胰腺癌移植瘤模型的靶向诊断与治疗。然而，临床中原位胰腺癌的治疗往往面临生理位置更隐蔽、微环境更复杂的问题。因而亟需一种靶向性更强、靶区释药更突出的诊疗因子来进一步提升胰腺癌的治疗效果。近期实验验证：10nm以下USPIO不但能增强MRI对比度，还可在射频磁场中产生磁热效应，使包裹它的温敏载体变形而迅速释放药物。另外，已有研究显示，ATF多肽可以特异结合胰腺肿瘤及其间质中过度表达尿激酶受体，具有靶向性好、穿透性强的特点。由此，本研究拟构建ATF多肽介导、共载IONP与5-氟尿嘧啶的多功能脂质体ATF-(USPIO/5Fu)-Lip，并开展针对原位胰腺癌模型的靶向显影及定位给药治疗，以期为胰腺癌的综合诊治提供新的方法。

影像对比度低、化药敏感性差是胰腺癌临床诊疗的主要难题，常致患者贻误诊断与治疗时机。本课题组以共载MR对比剂USPIO和化药5-氟尿嘧啶的胰腺癌靶向纳米药物系统，该纳米药物成功地实现了小鼠胰腺癌移植瘤模型的靶向诊断与治疗。由于胰腺癌的治疗往往面临生理位置更隐蔽，生理环境更复杂的问题。亟需一种靶向性更强、靶区释药更突出的诊疗因子来进一步提升胰腺癌的治疗效果。本研究进一步采用可以特异结合胰腺肿瘤及其间质中过度表达尿激酶受体的ATF多肽修饰纳米药物，其粒径120nm、电镜圆整均一等性质表征，及其磁信号性质等影像学评价（磁豫率）；本项目还对其体内外靶向胰腺癌开展靶向显像治疗作用机制，显示出对胰腺癌具有靶向性好、穿透性强的特点。另外，项目还通过考察靶向纳米药物ATF-(USPIO/5Fu)-Lip的体内代谢分布与急性毒性器官损伤等实验，证明本项目载体能够安全无毒用于临床前动物研究，因此，本研究所构建ATF多肽介导、共载USPIO与5-氟尿嘧啶的纳米药物ATF-(USPIO/5Fu)-Lip，并开展针对胰腺癌模型的靶向显影及定位给药治疗，将有望为胰腺癌疾病的临床诊断与治疗提供一种新的有效策略。