基于调控骨微环境的锶掺杂羟基磷灰石纳米载药体系的构建及其在乳腺癌骨转移治疗中的基础研究

Skeleton is one of the most commonly and early metastatic sites for advanced breast cancer patients. Invading into the bone cavity, breast cancer cells in the bone microenvironment will break the balance between osteoblasts and osteoclasts and make a vicious cycle, which can lead to osteolysis and speed the invasion and metastasis of breast cancer cells. Currently, chemical drugs were used for inhibiting the proliferation, invasion and metastases of cancer cells, meanwhile some agents for regulating the proliferation and differentiation of either osteoblasts or osteoclasts were used for inhibiting the osteolysis caused by breast cancer bone metastasis. All these methods could only inhibit the vicious cycle from one part, but the complexity of bone microenvironment was ignored. Depending on the cancer metastasis and osteolysis disease in breast cancer bone metastasis, it is necessary to develop the novel safety and targeted drug for the therapy of breast cancer bone metastasis. Therefore, our project will construct a nanodrug delivery system based on Sr/HAP nanoparticle and loaded miR34a. Three cell types in bone microenvironment treated with the nanodrug delivery systems, we will study the proliferation, invasion and metastasis of breast cancer cells MDA-MB231, and the viability and differentiation of osteoblasts and osteoclasts in vitro, and further clarity the molecular mechanisms in breaking the vicious cycle. Then the therapy effects of the nanodrug delivery system in vivo will be evaluated on the animal model of breast cancer bone metastasis. These results are of great significance for providing significant basic data for the therapy of breast cancer bone metastasis in clinic.

骨骼是晚期乳腺癌患者最早且最常见的转移部位之一。乳腺癌细胞一旦入侵骨腔，会破坏骨微环境细胞之间的动态平衡，导致溶骨性病变并加速肿瘤细胞的侵袭和转移。目前临床上主要通过化疗药抑制癌细胞活性并抑制其进一步转移；通过调控骨微环境中的破骨细胞或成骨细胞活性和分化来抑制溶骨性病变。这些手段只能从单一方面抑制肿瘤细胞与骨细胞之间的恶性循环，却忽略了骨微环境的复杂性，急需找到新型安全靶向的治疗药物。基于此，本项目将构建一种具有亲骨性能并负载miR34a的Sr/HAP复合纳米载药体系，体外研究该纳米载药体系对乳腺癌细胞MDA-MB231活性、侵袭和迁移的影响，以及对成骨细胞活性和分化、破骨细胞样细胞形成的影响；并分析相关细胞因子的表达，明确该载药体系调控骨微环境的机制；建立乳腺癌骨转移裸鼠模型，进一步评价该载药体系在体内对骨转移的治疗效果。该研究结果将为临床治疗乳腺癌骨转移提供基础研究数据，具有重要意义。

骨骼是晚期乳腺癌患者最早且最常见的转移部位之一。乳腺癌细胞一旦入侵骨腔，会破坏骨微环境细胞之间的动态平衡，导致溶骨性病变并加速肿瘤细胞的侵袭和转移。目前临床上主要通过化疗药抑制癌细胞活性并抑制其进一步转移；通过调控骨微环境中的破骨细胞或成骨细胞活性和分化来抑制溶骨性病变。这些手段只能从单一方面抑制肿瘤细胞与骨细胞之间的恶性循环，却忽略了骨微环境的复杂性，急需找到新型安全靶向的治疗药物。基于此，本项目将构建一种具有亲骨性能并负载miR34a的Sr/HAP复合纳米载药体系，体外研究该纳米载药体系对乳腺癌细胞MDA-MB231活性、侵袭和迁移的影响，以及对成骨细胞活性和分化、破骨细胞样细胞形成的影响；并分析相关细胞因子的表达，明确该载药体系调控骨微环境的机制；建立乳腺癌骨转移裸鼠模型，进一步评价该载药体系在体内对骨转移的治疗效果。该研究结果将为临床治疗乳腺癌骨转移提供基础研究数据，具有重要意义。