动脉灌注载吉西他滨和氯沙坦的介孔二氧化硅纳米颗粒对胰腺癌的疗效

Pancreatic cancer is one of the five most lethal malignancies in the world. Gemcitabine, as a fist-line chemotherapeutic agent, did not significantly increase the survival rate of patients with pancreatic cancer. Researchs indicated that gemcitabine had a very short half-life with low drug concentration at the tumor site in vivo and abundant stroma of pancreatic carcinoma prevented drugs permeating into tumor cells. Therefore, we propose a hypothesis that the use of nanomaterials loading with the chemotherapy drugs and anti-stroma drugs, which will be injected through related arteries to improve local concentration of nanoparticles, prolong the action time and increase drug delivery, could break through the stroma obstacles and targeting tumor cells. To test this hypothesis, we will load chemotherapy drugs (gemcitabine) and anti-stroma drugs (losartan) within the channel of mesoporous silica nanoparticles encapsulated of USPIO and connected target molecules RGD on the silica surface. Regional arterial infusion will be used targeted therapy for rat pancreatic cancer in situ. We will use MRI to track drug distribution and monitor tumor response to the therapy. Stromal components such as collagen typeⅠ, hyaluronic acid, transforming growth factor will be determined by immunohistochemical. This method is expected to improve the chemotherapeutic effect, inhibit tumor growth, reduce side effects of drugs and prolong the survival period. This project will provide a new method for the treatment of pancreatic cancer.

胰腺癌是5大最致命的恶性肿瘤之一，吉西他滨作为胰腺癌的一线化疗用药未显著提高患者的生存率。研究表明吉西他滨的半衰期短、到达肿瘤的血药浓度低，以及胰腺癌丰富的纤维基质阻挡其进入肿瘤细胞是造成化疗效果不佳的主要原因。为此我们提出假说，利用纳米材料同时装载化疗药物和抗基质药物，经动脉灌注提高肿瘤局部纳米颗粒浓度、延长其作用时间以增加药物递送能够突破基质障碍实现化疗药对肿瘤的精准杀伤。本项目拟在前期制备的表面修饰靶向分子RGD、内部包裹超顺性磁氧化铁的介孔二氧化硅纳米粒子的孔道内同时装载化疗药吉西他滨和抗基质药氯沙坦，用区域动脉灌注的方法减少肝脾等器官的非特异性摄取，对大鼠原位胰腺癌进行靶向治疗，通过MRI追踪纳米药物分布并测量肿瘤大小，免疫组化测定基质Ⅰ型胶原、透明质酸、转化生长因子等表达水平。该方法有望提高胰腺癌的化疗疗效、抑制肿瘤生长、降低药物副反应，延长生存期，为胰腺癌的治疗提供新的思路。

胰腺癌是继支气管肺癌、前列腺癌（乳腺癌）、结直肠癌之后排名第4位的“癌症杀手”。吉西他滨作为胰腺癌的一线化疗用药并未显著提高患者的生存率，研究表明肿瘤丰富的纤维基质阻挡其进入肿瘤细胞是造成化疗效果不佳的主要原因。在国家自然科学基金青年基金的资助下，本研究在制备的包裹Fe3O4的磁性介孔二氧化硅多功能纳米颗粒孔道内分别装载抗胰腺癌基质药物氯沙坦和化疗药吉西他滨，对裸鼠移植瘤进行靶向治疗。结果表明载氯沙坦纳米药物能够减少基质I型胶原、透明质酸的合成，下调转化生长因子TGF-β1、结缔组织生长因子CCN2的表达，联合载吉西他滨纳米药物，增强了吉西他滨的化疗效果，一定程度上抑制了肿瘤的生长，这也为临床胰腺癌患者的治疗提供了一种新的思路，有望提高胰腺癌的化疗疗效，延长患者的生存期。