多功能磁性纳米给药系统对脑胶质瘤双模精准诊测和靶向治疗的研究

Malignant brain glioma is a kind of the most invasive tumor. The boundary tissue of brain tumor is much similar to the normal one , which makes the boundary can not be accurately detected by traditional techniques. So, it is extremely difficult to resect tumors entirely in clinical operation and subject to relapse after surgery. In order to improve the accuracy of preoperative and intraoperative diagnosis and to enhance the therapeutic efficiency, hollow porous magnetic nano drug delivery system will be prepared in this project. Peptides as the targeting ligands are modified on the surface of these drug delivery system. Then, both antitumor drugs and photosensitive prodrugs are loaded into hollow porous cavities, which will be delivered under dual-targeting mediation of applied magnetic field guidance and receptor-mediated transport mechanism and released at the appropriate locations. Photosensitive prodrugs which are sensitive and selective to the tumor cells can fluoresce under the light irradiation. We will take advantage of the fluorescent imaging and magnetic resonance imaging to realize the bimodal real-time diagnosis for the tumor size and boundary of brain glioma accurately. Meanwhile, under the light radiation, brain glioma can be treated by synergy of photodynamic therapy and chemotherapy. Overall, this project will create the bimodal real-time accurate diagnosis and synergistic treatment of photodynamic therapy and chemotherapy for malignant brain glioma.

恶性脑胶质瘤的侵袭性较强，肿瘤边缘和正常组织极为相近，传统诊断技术难以探测到肿瘤边界，严重影响手术切除效果，未完全切除的肿瘤术后极易复发。为了临床术前和术中更加精准探测肿瘤的边界并提高术后治疗效果，本项目拟构建具有可装载光敏剂前体药物和抗肿瘤药物的中空介孔磁性纳米给药系统，表面修饰具有靶向功能的多肽，在外磁场和多肽的双重靶向作用下实现药物的靶向递送和定位释放。光敏剂前体药物对肿瘤细胞具有高度的敏感性和选择性，经光辐照后发出荧光，利用此荧光并辅助MRI实现双模成像，实现临床术前和术中更为精准地探测脑肿瘤的边界，提高手术切除效果。术后给予药物治疗降低脑瘤复发。基于该纳米系统装载的化疗药物和光敏剂前体药物，在光辐照作用下发挥光动力学疗法和化疗协同作用。创新性在于利用双靶向磁性纳米给药系统的荧光和MRI双模成像手段以及化疗和光动力学疗法协同作用对恶性脑胶质瘤进行实时精准诊测和靶向治疗。

恶性脑胶质瘤是中枢神经系统中最严重的一类疾病，具有高发病率、高复发率、高死亡率和低治愈率的特点，传统上，临床治疗恶性脑胶质瘤主要采取手术切除、放射治疗和化学疗法等技术手段，但是，由于肿瘤边界与正常组织极为相近，手术技术难以完全切除，残留的肿瘤在原发部位仍然会复发，而采用放射治疗，光辐射能量会严重损害正常组织。在所有治疗手段中，细胞毒类药化学疗法是最为可行的方法之一。但是，由于血脑屏障和血瘤屏障的存在，使得100 %的大分子药物和98 %以上的小分子药物难以跨越血脑屏障，从而使得恶性脑肿瘤疾病的治疗困难重重。.随着纳米技术在生物医学领域的广泛渗透与发展，靶向性纳米给药系统为恶性脑胶质瘤的诊治开辟了新途径。基于此，本课题的主要研究内容是构建一种具有外磁场被动靶向和受体介导的主动靶向机制的多功能磁性纳米给药系统，深入研究此纳米给药系统的在体外和体内水平上对恶性脑胶质瘤精准诊断和靶向治疗的效果。实验结果表明，采用乳化-溶剂挥发法制备的多功能磁性纳米给药系统具有较好的单分散性、磁响应性、超顺磁性、以及较高的横向弛豫率等特点。在体外细胞水平上的研究表明，外磁场导引和转铁蛋白受体介导的双靶向机制有利于此纳米给药系统更好地跨越血脑屏障并内吞进入恶性脑胶质瘤细胞内，使得细胞周期阻滞于G2/M期，自噬囊泡较多，线粒体膜电位降低，细胞凋亡率较高；并且，此载体具有较好的MR成像的对比度；同时，在体内动物水平上的研究得出，双靶向机制能够较好地促进此纳米给药系统靶向富集于恶性脑胶质瘤目标区，增强了肿瘤组织与正常组织的对比度，较好地抑制肿瘤增殖并延长动物存活时间。.总之，此课题的开展将为下一步开展临床诊治恶性脑胶质瘤奠定了基础，构建的纳米给药系统将在生物医学领域具有广阔的应用前景。