纳米材料复合miR-141-3p靶向肿瘤内环境防治PCa骨转移的作用机制研究

Prostate cancer (PCa) is one of the most vulnerable tumors with bone metastasis. Distant organ metastasis indicates poor clinical prognosis. However, the commonly used therapies in clinic still cannot effectively prevent bone metastasis in PCa. The development of epigenetic modification for nanomaterials brings hope to the prevention and treatment of bone metastases in PCa. However, the injection of genetically modified nanoparticles into the body to prevent and treat tumors is a complex process that is affected by multiple factors. Therefore, only by finding out the cellular and molecular mechanism and the influencing factors in this process can the prevention and treatment of bone metastases in PCa be effectively improved. Our previous study has showed that miR-141-3p affects the occurrence of bone metastases in PCa through regulating the NF-κB signaling pathway, suggesting that miR-141-3p can be used as a molecular target for the prevention and treatment of bone metastases in PCa. Previous studies have also revealed that manganese-doped calcium phosphate nanoparticles synthesized by a natural biomolecule (adenosine triphosphate) as a phosphorus source is characterized by highly efficient gene loading, controllable targeting and dynamic monitoring of gene release. This study investigates the effect and mechanism of miR-141-3p-modified nanomaterials in the safe and effective prevention and treatment of bone metastases in PCa under an intratumoral environment, providing new ideas and strategies for the better prevention and treatment of bone metastases in PCa using designed functional biomaterials.

前列腺癌（PCa）是最易发生骨转移的肿瘤之一，发生远处器官转移提示临床预后较差，但目前临床上常用治疗方法仍不能有效防治PCa骨转移。表观遗传学修饰纳米材料学的发展为PCa骨转移的防治带来希望，但基因修饰纳米颗粒注入体内具有防治肿瘤功能活性是一个多因素影响的复杂过程，只有弄清这一过程所发生的细胞和分子机理及其影响因素的关键科学问题，才能有效提高PCa骨转移的防治效果。前期研究发现miR-141-3p通过调控NF-κB信号通路影响PCa骨转移的发生，提示其可作为防治PCa骨转移的基因分子靶标。前期研究还发现，以天然生物分子（三磷酸腺苷）为磷源合成的锰掺杂磷酸钙纳米颗粒,具有基因能高效装载、靶向可控及动态监测基因释放等优势。本项目将通过研究探索miR-141-3p修饰纳米材料在肿瘤内环境条件下，安全有效发挥PCa骨转移防治作用及机制，为功能化设计生物材料能更好防治PCa骨转移提供新思路及新策略。

前列腺癌(prostate cancer，PCa)是最易发生骨转移的肿瘤之一，目前临床上常用的治疗方法仍不能有效防治PCa骨转移。表观遗传学及生物纳米材料的不断深入研究为PCa骨转移的防治带来希望，但基因修饰纳米材料发挥抗肿瘤活性是一个多因素影响的复杂过程，具体机制尚不清楚。本项目通过共价偶联及静电吸附法构建了复合miR-141-3p及叶酸的氧化铁纳米颗粒(miR-141-3p+NPs+FA)，该复合纳米颗粒的粒径＜100nm且miR-141-3p的吸附率高；进一步探索miR-141-3p+NPs+FA对前列腺癌骨转移瘤细胞(PC-3细胞)恶性生物学行为的影响，结果发现miR-141-3p+NPs+FA可抑制PC-3细胞的侵袭能力，并通过调控TRAF1、Bax及Bcl-2蛋白的表达促进PC-3细胞凋亡。同时，本项目优化方案，通过调整模板剂、PH值及掺锰比例等因素，构建了以ATP为有机磷源的掺锰磷酸钙纳米颗粒，该掺锰磷酸钙纳米颗粒呈类球形、表面具有无定型磷酸钙薄壳、粒径＜100nm并携带正电荷。此外，针对肿瘤转移等因素导致的骨缺损修复难题，还构建了可缓慢释放蛋白质、促进成骨细胞增殖及成骨分化的纳米磷灰石涂层藻酸盐/GelMA中空仿生支架。但纳米材料吸附微小RNAs(microRNAs，miRNAs)靶向防治PCa骨转移的具体机制有待优化实验方案后进一步研究探索。总之，本研究构建了复合miR-141-3p及叶酸的氧化铁纳米颗粒并探索其对PC-3细胞恶性生物学行为的影响，同时还优化了以ATP为有机磷源的掺锰磷酸钙纳米颗粒的制备方案，为功能化设计表观遗传学修饰纳米材料防治PCa骨转移提供了前期实验参考。

内容获取失败，请点击重试