仿生介孔生物玻璃纳米球的研制及对乳腺癌骨转移瘤的抑制效应和机制探讨

The construction of a novel drug-delivery system for breast cancer bone metastases, which endowed with tumor-targeted and tumor-suppressed, is the frontal hotspot and difficulty in the nano-biomedical field nowadays. In this project, we innovatively proposed the ideas about how to improve the therapeutic efficacy for breast cancer bone metastases in clinical issue as two respects. On one hand, MBG nanospheres that developed with high specific surface area, high drug-load and bio-safety, were endowed with the two biomimetic functions including immune escape and homologous target through the remodeling of breast cancer cell membranes in their surface. It revealed the biomimetic effect regulated on the biological behavior of MBG nanospheres, and played a key role in extending the circulation time and enhancing the tumor targeting of those. On the other hand, from different levels of histology, cytobiology and molecular biology, the pH-responsive of MBG delivery driven by tumor microenvironment acted as an entry point to illuminate the delivery’s role in the regulation of calcium influx-mediated breast cancer cell apoptosis and intracellular essential proteins expression, and to demonstrate the biological effects and mechanism of the active inhibition effects of breast cancer cell and breast cancer bone metastases induced by MBG nanospheres. So in our project, we try to solve a series of key scientific problems about MBG nano-biomimetic drug delivery system including the efficient delivery, high targetability and active antitumor for breast cancer bone metastases. This study will fill the gaps at home and abroad in the field of research on MBG nanospheres as a functional drug delivery. Furthermore, the project has an important scientific significance and potential application value, which creates the premise for promoting the therapeutic efficacy of breast cancer bone metastases.

构建兼具肿瘤靶向和主动抑瘤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。本项目围绕如何提高乳腺癌骨转移瘤治疗效果这一问题，创新性地提出：在制备高比表面积、高载药量、生物安全的介孔生物玻璃(MBG)纳米球表面重构乳腺癌细胞膜，赋予其免疫逃逸和同源靶向2大仿生功能，揭示仿生效应在延长载体体内循环时效和提高肿瘤靶向聚集中的作用途径及生物学行为规律；同时以肿瘤微环境介导的MBG载体pH响应性为切入点，从整体、细胞和分子生物学层面上，揭示载体诱发钙内流介导的乳腺癌细胞凋亡和对胞内关键蛋白的调控作用，分别阐明载体主动抑制乳腺癌细胞和乳腺癌骨转移瘤的生物学效应及其机制。最终试图解决在治疗乳腺癌骨转移瘤中MBG纳米仿生递药系统的体内高效递送、靶向聚集和主动抑瘤这些关键科学问题，填补国内外在功能化药物载体研究领域的相关空白，为提高乳腺癌骨转移瘤的治疗效果创造前提，项目具有重要科学意义和潜在应用价值。

构建兼具肿瘤靶向和主动抑瘤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新型仿生MBG纳米递药系统，探讨MBG结构与载药性能的关联性，并以肿瘤微环境介导的MBG载体pH响应性为切入点，从整体、细胞和分子生物学不同层面上，系统解释载体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，验证经细胞膜重构的仿生MBG纳米球的免疫逃逸和同源靶向效应，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）利用CPB作为MBG合成过程中的结构诱导剂，有效增加表面活性分子间距，提高MBG纳米球的比表面积和载药性能，且该MBG纳米球具有良好pH敏感药物释放和离子释放功能，为后续构建仿生纳米药物递送系统核心提供了重要支持；（2）MBG纳米球利用响应肿瘤酸性微环境释放自身钙离子的特性，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）经细胞膜包覆的MBG纳米球显示出良好的免疫逃逸和肿瘤靶向聚集功能，其中相较于乳腺癌细胞膜包覆MBG纳米球，巨噬细胞膜包覆MBG纳米球肿瘤靶向聚集效应更为明显，由此选择巨噬细胞膜包覆MBG纳米球以构建载药仿生MBG纳米球；（4）载药仿生MBG纳米球具有良好的药物缓释功能和持续杀伤肿瘤效应，通过诱导肿瘤组织发生广泛的细胞凋亡实现肿瘤抑制效果，同时载药仿生MBG纳米球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MBG纳米仿生递药系统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。