融合细胞膜包覆介孔生物玻璃/硫化铜纳米复合物的构建及对非小细胞肺癌的抑制效应和其机制

To construct a new nano-biomaterials for non-small-cell lung carcinoma, which endowed with tumor-targeted and tumor-suppressed, has become the crucial problem to be solved immediately in the field of nanotechnology and biomedicine. In this project, we innovatively proposed the ideas as follows, mesoporous bioactive glass (MBG) nanospheres are set as core, and in situ control the growth of copper sulfide (CuS) on the surface of nanospheres, to develop MBG/CuS nanocomposites with specific tumor inhibition and photothermal effect. Further, the surface of MBG/CuS nanocomposites were remodeled with the hybrid cytomembrane that derived from platelet and non-small-cell lung carcinoma cells, which played a key role in extending the circulation time and enhancing the tumor targeting of nanocomposites. Meanwhile, from different levels of histology, cytobiology and molecular biology, the calcium homeostasis of tumor cell acted as an entry point to illuminate the nanocomposites role in the regulation of calcium ions channels and transporters mediated inhibition effects and mechanism of non-small-cell lung carcinoma. Finally, we try to solve the key scientific problems about the hybrid cytomembrane coated MBG/CuS nanocomposites including a high-efficiency circulation, accurate targeting amd multi-functional killing for non-small-cell lung carcinoma. This study will fill the gaps at home and abroad in the field of research on MBG/Cus nanocomposites as functional nano-biomaterials, and improve the therapeutic efficacy of non-small-cell lung carcinoma by evading primary and acquired drug resistance.

构建具有精准肿瘤靶向和主动抑瘤功能的纳米生物材料是纳米技术与生物医学领域中的热点和难点。本项目围绕如何提高非小细胞肺癌治疗效果这一问题，创新性地提出：以介孔生物玻璃(MBG)纳米球为基础原位可控修饰合成硫化铜(CuS)，制备兼具特异性肿瘤抑制和光热效应的MBG/CuS纳米复合物，并在MBG/CuS纳米复合表面重构血小板-非小细胞肺癌来源的融合细胞膜，使其具有体内长循环时效和精准肿瘤靶向的生物学行为规律；同时以肿瘤细胞钙稳态为切入点，从整体、细胞和分子生物学不同层面上，揭示纳米复合物调控钙离子通道和转运受体介导的非小细胞肺癌抑制效应及其机制。最终试图解决在治疗非小细胞肺癌中融合细胞膜包覆MBG/CuS纳米复合物的体内高效循环、精准靶向聚集和多功能协同杀伤肿瘤等关键科学问题，填补国内外在功能化纳米生物材料研究领域的相关空白，为规避原发性耐药和获得性耐药、提高非小细胞肺癌的治疗效果创造前提。

构建兼具肿瘤靶向和免疫逃逸功能的纳米递药系统是当今纳米生物医药领域的热点和难点。本项目聚焦构建具备免疫逃逸、肿瘤靶向聚集和主动抑瘤功能的细胞膜包覆介孔生物玻璃（MBG）纳米复合物递药系统，探讨MBG结合聚多巴胺负载不同类型金属离子的可行性，并以MBG纳米颗粒的pH响应肿瘤微环境为切入点，从整体、细胞和分子生物学不同层面上，系统解释纳米颗粒诱发钙内流介导的凋亡途径在抑制肿瘤效应中的生物学作用及机制，验证细胞膜包覆MBG纳米颗粒的免疫逃逸和肿瘤靶向聚集效应，阐明其靶向肿瘤聚集和肿瘤抑制的作用途径和生物学行为规律，为解决在肿瘤治疗中MBG纳米递药系统高效递送和功能化的关键问题提供科学依据。研究发现：（1）本项目引入聚多巴胺涂层包覆MBG纳米颗粒，并在涂层过程中引入铜源和钴源，有效实现含铜-钴的MBG纳米复合物的合成，为后续构建细胞膜包覆MBG纳米复合物递药系统提供了重要的支持；（2）MBG纳米颗粒利用响应肿瘤酸性微环境释放自身离子的特性，特异性促使肿瘤细胞钙离子通道和CaSR活化，介导钙离子内流，促使肿瘤细胞内钙超载，继而活化Calpain-1来切割STIM1和Bcl-2，破坏细胞的内稳态，导致以Caspase-3为代表的瀑布式凋亡级联反应，实现特异性的肿瘤抑制作用；（3）细胞膜包覆MBG纳米颗粒显示出良好的免疫逃逸和肿瘤靶向聚集功能，其中巨噬细胞膜包覆MBG纳米颗粒显示出优异的髓系细胞（包括单核细胞、中性粒细胞和树突状细胞）逃逸效应和肿瘤靶向效应；（4）细胞膜包覆MBG纳米递药体系具有良好的药物缓释功能和持续杀伤肿瘤效应，通过诱导肿瘤组织的凋亡实现肿瘤抑制效果，细胞膜包覆MBG纳米递药体系未引起明显的全身毒性反应，提示其具有良好的生物安全性能。综上所述，本项目构建的细胞膜包覆MBG纳米递药体系显示出体内高效递送、靶向聚集和协同药物主动抑瘤功能，填补国内外在功能化药物载体研究领域的相关空白，为提高肿瘤的治疗效果创造前提，具有一定的临床潜在应用价值。