癌症微环境调控性钙镁硅系陶瓷材料体系的构建与其抑癌效能研究

Aimed at solving the difficult and critical problems in cancer anti-recurrence and metastasis during the current clinical treatment, this project is innovatively proposed to utilize the ionic dissolution products of CaO-MgO-SiO2-based bioceramics to regulate the extracellular microenvironment of cancer cells, and further to inhibit the growth and metastasis of tumor. Based on the physiological characteristics of cancer and the preliminary research foundation, the academic idea and technology route in this project are proposed as follows: the interaction effect as well as its cellular and molecular biological mechanisms of the influences of Ca, Mg and Si ions as well as ion combination on human lung carcinoma epithelial cells and normal lung epithelial cells will be systematically researched firstly, to find out the optimal ion combination and concentration range which are beneficial to anti-cancer efficacy without toxicity to normal cells. Based on the above, a novel CaO-MgO-SiO2-based multiphase bioceramic powder system with controlled ion dissolution and biological response behavior is tried to be constructed. The structure-activity relationship among the chemical composition, crystal structure, particle size range, ion release behavior and cell biological effect will be explored. On this basis, a CaO-MgO-SiO2-based bioceramic power system with the potential of tumor suppression will be optimized. And its ability to inhibit tumor growth through continuous ion release in vivo, the efficacy of preventing metastasis, as well as the dose-effect relationship between the material usage an its inhibition effect on tumor, will be all investigated. Moreover, the mechanism of the anti-cancer action of this material at cellular and molecular levels will be emphatically studied and analyzed, which must lay a theoretical and experimental foundation for developing new safe and high effective anticancer materials.

针对癌症临床治疗过程中易发生复发转移这一难题，创新性地提出利用CaO-MgO-SiO2系生物陶瓷离子溶出物调控癌细胞胞外微环境，进而抑制肿瘤生长和转移。基于癌症的生理学特征分析和前期研究基础，深入系统研究钙、镁、硅离子及离子组合对人肺腺癌细胞和正常肺上皮细胞的交互作用效应及细胞分子生物学机理，确立抑癌促分化而无毒副作用于正常细胞的最佳离子组合及浓度范围，并以此为基础构建一种离子释放行为和生物学响应可控的新型钙镁硅系多相复合陶瓷粉体体系。探索粉体化学组成-晶相结构-粒径范围-离子释放行为-细胞生物学效应间的构效关系，优选出一种粉体体系，考察其在体内生理环境下持续释放离子抑制肿瘤生长的能力、预防转移灶出现的效能及肿瘤抑制量效关系等，并从细胞、分子水平上阐释作用机理，为研发新型安全高效抗癌材料奠定理论基础和实验依据。

本项目针对当前癌症临床治疗现存难点问题，在前期研究基础，深入系统了研究高低浓度范围内的单一钙、镁、硅离子及离子组合对癌细胞和正常细胞的交互作用效应及不同的生物学机理，确立了抑癌促分化而无毒副作用于正常细胞的最佳离子组合及浓度范围。同时，选择四种CaO-MgO-SiO2系三元单相陶瓷（钙镁橄榄石、透辉石、镁黄长石、镁蔷薇石）作为研究对象，利用溶胶-凝胶法制备出生物陶瓷粉体，研究其离子溶出行为及影响因素，重点从化学组成和晶体结构两个本质特性探讨了该体系生物活性陶瓷粉体的离子溶出规律及本质特性。基于以上结果，参考CaO-MgO-SiO2三元系统相图，构建了三种多相陶瓷体系，从材料本征特性和物化性质（化学组成、晶相结构、粒径等）角度研究其离子释放行为，筛选出溶出离子在前期所得的有效作用范围内的陶瓷粉体C2。最后，通过将其与体外癌细胞及正常细胞共培养评价其体外抑癌特性及生物相容性。构建裸鼠皮下荷瘤模型评价其体内安全抑瘤效能，发现与对照组相比，材料实验组肿瘤组织的平均体积明显小很多倍。体内外生物学实验结果显示该材料具体优良的抑瘤效能。