低剂量空心氧化锰复合结构探针用于肿瘤早期诊断和靶向治疗

The applications of nanomaterials in early diagnosis and targeted therapy of cancer have been hot and key issues in biomedical research. However, at present, there are some problems in NPs-based theranostic reagents that need to be solved, such as non-specific treatment, large dose and side effects, particles too large to metabolize. Hence, the concepts of "synergistic enhancement" and "controllable release" for early diagnosis and targeted therapy of cancer were introduced. We will construct hollow manganese oxide nanostructures, which internally loaded with ultrasmall gadolinium oxide nanoparticles and anticancer drugs. Gadolinium oxide and drugs are controllably released due to the collapse of manganese oxide shell in the weak acidic environment of the tumor region. The released ultrasmall gadolinium oxide can significantly increase relaxation rate and reduce diagnostic dose; Those tiny manganese oxide fragments and final Mn2+ formed after collapse can synergistically enhance the contrast effect of magnetic resonance imaging (MRI); The released anticancer drugs can achieve targeted treatment of tumor. Meanwhile, tiny manganese oxide fragments, Mn2+ and ultrasmall gadolinium oxide all can be rapidly excreted from the body to ensure the biological safety. Finally, we realize low-dose diagnosis and controlled drug release under the premise of biosafety, and provide referential ideas for early diagnosis and targeted therapy of cancer.

纳米材料在癌症的早期诊断和靶向治疗中的应用一直是生物医学研究的热点和重点问题。然而，目前纳米诊疗剂存在非特异性治疗、剂量和毒副作用大、颗粒大不易代谢排出等亟待解决的问题。基于此，本项目拟引入“协同增强”和“可控释放”的概念，用于癌症的早期诊断与靶向治疗。我们将构建空心氧化锰纳米结构，并在其内部装载超小的氧化钆纳米颗粒和抗癌药物。在肿瘤的弱酸性环境下氧化锰外壳崩塌，释放氧化钆和抗癌药物，实现可控释放。超小的氧化钆可以显著提高磁共振弛豫率并减少诊断使用剂量；降解后形成的氧化锰小碎片和最终形成的Mn2+可协同增强磁共振显影效果；释放的抗癌药物可实现肿瘤部位的靶向治疗。同时，氧化锰小碎片、Mn2+和超小氧化钆均可从体内快速排出，保证生物安全性。最后，在生物安全的前提下实现低剂量诊断和药物的可控释放，为癌症的早期诊断和靶向治疗提供借鉴性的研究思路。

目前，纳米诊疗剂仍然存在着剂量和毒副作用大、非特异性积累、不易代谢和生物降解的问题。本项目通过几个子课题针对性地解决了上述问题，同时实现了癌症的早期诊疗。我们制备了不同形状的氧化锰纳米结构，由于其超高的灵敏度，大大减小了使用剂量，因而降低了毒副作用，实现了癌症的早期灵敏诊断；我们构建了具有空心结构的多孔核壳型氧化锰载药系统，将多孔氧化锰诊断试剂和治疗药物（如核酸抗癌药物）两部分巧妙地结合起来，达到可控药物释放的目的，实现协同增强诊断和治疗作用。我们开发了基于黑磷量子点的近红外荧光纳米诊疗探针，其具有良好的生物降解性，可以在肾脏中特异性积累，且可以有效保护组织在急性肾损伤中免受活性氧介导的损伤；我们合成了两种可激活的19F磁共振成像分子探针，它们可以同时在体内检测活性氧和进行深层组织成像。