肿瘤微环境响应的双模态内源增效Cat/PEG-MnO2纳米诊疗剂研究

It is a big challenge to realize precise diagnosis and efficient therapy of cancer for clinical medicine. Design and fabrication of nanotheranostics with concurrent diagnostic and therapeutic functions provide a solid base for precise therapy of cancer. We have preciously successfully synthesized HIFU synergistic agents based on PLGA and organic/inorganic hybrid mesoporous organosilica nanoparticles. But compared to endogenous synergistic nanotheranostics, ectogenic liquid - vapor phase change material is needed which could bring security and targeting problems. Based on the theory that MnO2 nanosheet collapse under weak acidic condition to enhance MRI and Catalase catalytic decompose hydrogen peroxide in situ to produce oxygen to enhance ultrasound contrast, we propose that the new Cat/PEG-MnO2 nanosheets are featured with tumor microenvironment-sensitive bimodal endogenous ultrasound/MRI dual-modality imaging and HIFU synergistic function. To verify it, we will conduct the researches on the control of composition and nanostructure of Cat/PEG-MnO2 nanosheets, optimize the desirable nanostructure parameters, test the relationship of nanostructure-composition-ultrasound theranostic function, and reveal the mechanism of tumor microenvironment-sensitive ultrasound/MRI-guided HIFU synergistic therapy. This project is based on the new viewpoint of tumor microenvironment, which will provide the base for revealing the mechanism of nanotheranostic-based tumor precise imaging and intrinsic HIFU synergistic therapy, and provide the new strategy for precise imaging and efficient therapy of tumor.

设计制备兼具诊断和治疗为一体的纳米诊疗剂，是实现肿瘤精准治疗的基础。前期虽已成功制备出PLGA和有机/无机杂化介孔有机硅基HIFU增效剂，但与内源增效靶向纳米诊疗剂相比，需外界引入液-气相变物质，易产生安全性和定位难等问题。基于MnO2纳米片在弱酸条件下发生裂解可增强MRI造影以及过氧化氢酶（Catalase）原位催化分解产生氧气增强超声造影，为此，提出假说：Catalase负载的MnO2纳米片(Cat/PEG-MnO2)具有肿瘤微环境响应的双模态HIFU内源增效功能。为验证假说，项目拟开展Cat/PEG-MnO2纳米片化学组成和结构的调控，筛选最佳结构参数，检测纳米结构、组成、超声诊疗性能三者关系，明确肿瘤微环境响应的超声/MRI双模态影像导航下的HIFU增效的精确调控。本研究立足肿瘤微环境响应新视点，旨在揭示靶向纳米诊疗剂内源性激发HIFU增效机制，为肿瘤精准成像和高效治疗提供新思路。

针对目前肿瘤精准治疗的临床要求，本项目完成了包括MnOx/Ta4C3−SP诊疗剂，MnOx/TiO2-GR纳米声敏剂，MnOx/Ti3C2纳米诊疗剂，Cu2-xS-PEG纳米催化剂等在内的多种新型纳米诊疗剂的制备，并对其成像影/增效影响因素进行了探讨与机制研究；成功对多功能诊疗剂进行了包括光声成像，核磁成像在内的多模态成像性能进行了检测，并系统地对其体内外的生物安全性进行了评价；探讨了多种新型纳米诊疗剂的多模态成像最佳参数，以及增效治疗效果评价，并全面地研究了以MnOx/Ta4C3−SP诊疗剂为代表的消融增效性能，并获得了最佳的治疗参数，可有效提高肿瘤消融效率。此外，本研究进行过程中基于所得结果，还创新性地将声动力治疗，光热治疗等研究热点与多功能超声诊疗剂相结合，进一步拓展了的研究领域，对纳米医学的发展和精准治疗提供了切实的理论基础和可靠的实验依据，并促进了医学和材料学的交叉学科融合发展，为实体瘤的治疗提供了新策略和新思路。