多功能磁共振对比剂CD133/tLyP1-MeS@PD-Angiopep2靶向成像及热疗脑胶质瘤的研究

Gliomas are fatal diseases with extreme malignancy, high recurrence rate and poor therapeutic effect. These are attributed to the vestigital of surgery on account of unclear boundary caused by the invasive growth of gliomas and resistance to radiation and chemotherapy of glioma stem cells. The mild hyperthermia on basis of multifunctional targeted contrast agent provides novel method for the treatment of gliomas. In our project, natural chemotherapy drugs melanin from sepia and polydatin are chosen as the main raw materials to design and synthesize two kinds of multifunctional targeted contrast agents, CD133-MeS@PD-Angiopep2 and tLyP1-MeS@PD-Angiopep2, for further targeted MRI imaging and photothermal therapy on gliomas.The former agent targets the glioma stem cells using CD133mAb while the latter targets glioma non-stem cells on account of tLyP1. As a consequence, the combination of aforementioned two agents can damage glioma stem cells and non-stem cells to achieve the purpose of efficient treatment and prevention of recurrence. Furthermore, our team intends to reveal the therapeutic effects and relevant molecular mechanisms of these two multifunctional targeted contrast agents on glioma cells, which can provide theoretical basis for therapy of gliomas.

脑胶质瘤恶性度大，复发率高，治疗效果差。主要原因是脑胶质瘤浸润性生长导致肿瘤边界难以明确，使手术无法完整切除，以及脑胶质瘤干细胞对放化疗具有抵抗性。基于多功能靶向对比剂发展起来的亚高温热疗为脑胶质瘤的治疗提供了新的方法。本项目拟采用天然化疗药物乌贼黑色素和虎杖苷为主要原料，设计合成CD133-MeS@PD-Angiopep2和tLyP1-MeS@PD-Angiopep2两种多功能靶向对比剂，来实现对脑胶质瘤的靶向MRI成像和光热治疗。前者以CD133mAb靶向脑胶质瘤干细胞，后者以tLyP1靶向脑胶质瘤非干细胞，联合使用两种靶向对比剂以实现对脑胶质瘤细胞的普遍治疗、重点杀伤，达到有效治疗、预防复发的目的。此外，我们拟进一步探究这两种多功能靶向对比剂对脑胶质瘤的治疗效果及相应的分子机制，为脑胶质瘤治疗的研究提供理论依据。

胶质母细胞瘤是最常见的颅内恶性肿瘤，具有恶性程度高、侵袭性强、预后差、高复发率等特点，预后不良的主要原因是胶质母细胞瘤浸润性生长导致肿瘤边界难以明确，使手术无法完整切除，以及脑胶质瘤干细胞对放化疗具有抵抗性。基于多功能靶向对比剂发展起来的光热治疗为胶质母细胞瘤的治疗提供了新的方法。本项目组成功合成可进行磁共振成像和光热治疗的多模态纳米粒子，并验证其生物安全性可靠、稳定性良好以及较好的光热转换效率。此外，发现了光热治疗通过抑制致癌MSH6-CXCR4-TGFB1反馈环及其下游的p-STAT3/Slug和p-Smad2/3/ZEB2信号通路有效治疗胶质母细胞瘤；验证了虎杖苷通过抑制AKT/STAT3-FOXO1信号传导途径，并减少增殖、凋亡和上皮间质转化相关的迁移和侵袭而发挥抗肿瘤作用；提出SOX2-AKT/STAT3-Slug信号通路可作为治疗胶质母细胞瘤的新靶点。