基于氧化石墨烯/黑磷复合水凝胶的抗肿瘤研究

Graphene oxide (GO) based hydrogel nanomaterials have displayed good targeting as well as local controlled release behaviors in photothermal therapy for cancer. However, lower photothermal covert efficiency of GO hydrogel requires larger irradiation power of near-infrared light (NIR), usually 1-2 W/cm2, resulting in damage for both tumor cells and normal tissues and cells. On the other hand, black phosphorus (BP), a two-dimensional material, has recently shown big potential in photothermal therapy for cancer due to its excellent photothermal property, biocompatibility and biodegradability. Poor targeting and stability of BP determined by its chemical structures yet restrict its application. Taking the individual merit as well as limitation of GO hydrogel and BP into account, the project intends to gelate GO with BP to simultaneously enhance the photothermal property of GO hydrogel and improve the stability of BP, realizing high-performance photothermal therapy at low irradiation power. Based on this, anticancer drugs doxorubicin (DOX) will be introduced and an anticancer system based on hybrid hydrogel of GO/BP/DOX will be built. The local controlled release behavior of DOX and BP’s stability under photothermal context will be investigated systematically. By means of build tumor cell as well as animal models, biosafety, targeting, photothemal efficiency, retention effect and local chemotherapy of GO/BP/DOX hybrid hydrogel will be evaluated, which aims at exploring its application value in cancer therapy.

氧化石墨烯（GO）基水凝胶纳米材料在肿瘤光热治疗中显示出了较好的靶向性和局部缓控释行为等；然而，其较低的光热转换效率使得所使用的近红外光辐照功率往往较大（1-2 W/cm2），这在损伤癌细胞的同时也损伤了正常组织和细胞。另一方面，二维材料黑磷（BP）因其优异的光热性、生物相容性以及可降解性在肿瘤治疗中显示出了较大的潜力。然而，BP的化学结构决定了其靶向性和稳定性较差。正是鉴于GO水凝胶和BP各自的优缺点，本项目拟将二者进行复合“凝胶化”，以同时提高GO的光热性能和BP的稳定性，实现低辐照功率下的高效光热疗效。在此基础上，进一步引入抗癌药物阿霉素（DOX），构建GO/BP/DOX复合水凝胶抗癌给药体系，系统研究光热行为下DOX的局部缓控释行为及BP的稳定性。进一步通过建立肿瘤细胞和动物模型，评价复合水凝胶的生物安全性、靶向性、光热特性、肿瘤滞留性及局部化疗性能等，探索其在肿瘤诊疗中的应用。

二维材料黑磷具有高光热性和高生物相容性，但化学稳定性较差；氧化石墨烯具有优异的化学稳定性，但光热性能较低。本项目循序渐进地开发了四类兼具高光热特性、高生物相容性和高化学稳定性的纳米复合材料体系，包括黑磷/氧化石墨烯（BP/GO）复合水凝胶、黑磷/纤维素复合水凝胶、MXene/纤维素/DOX复合水凝胶以及碲-硒纳米径向异质结材料，并详细研究了相应体系的物理特性和抗肿瘤活性，其主要研究结果如下：.1）.在BP/GO复合水凝胶体系中，BP和GO的“三维凝胶化”，不仅可将BP纳米片“束缚”于GO的片层间，从而“隔绝”了空气和水，进一步提高了BP的化学稳定性，而且所得三维（3D）BP/GO材料具有近红外光下的低辐照（0.2 和0.5 mW/cm2）高光热特性，这为BP化学稳定性的提高提供了新的研究思路和方向；.2）.以绿色高分子纤维素为3D框架、BP为光热试剂，成功开发出了3D BP“果冻”。研究表明，BP“果冻”具有优异的生物相容性和光热性以及较高的抗肿瘤活性；然而，由于肿瘤的3D性和复杂性，基于BP“果冻”的单模态光热治疗（以“瘤内注射”的给药方式）无法完全消除肿瘤，这表现在肿瘤的术后复发现象；.3）.以绿色高分子纤维素为3D框架、碳化钛型MXene纳米片为光热试剂、盐酸阿霉素（DOX）为经典抗癌药物，成功开发出了智能光热抗肿瘤水凝胶材料。研究表明，MXene-DOX@纤维素材料具有智能光响应性、光控释药性、高光热特性等；采用“瘤内注射”的给药方式，采取热疗-化疗联合治疗模式，可最终完全消除肿瘤，且无术后肿瘤复发现象；.4）.以碲（Te）相为核、以硒（Se）相为壳，成功开发了高效抗肿瘤的Te-Se纳米径向异质结材料。研究表明，Te-Se材料具有高光热转换效率、高化学稳定性、高生命安全性以及高靶向性；采用“静脉注射”的给药方式，仅单模态光热抗肿瘤可完全消除肿瘤，且无复发的现象；此外，借助于其高效的光热特性和化学稳定性，Te-Se材料也被成功应用于太阳能光热海水淡化领域中。.