溶骨性骨转移瘤是恶性肿瘤常见并发症，转移瘤生长使骨重吸收加剧，引起顽固性骨痛和病理性骨折，化疗效果不佳。阿仑膦酸钠（ALN）对骨基质有很强的亲和力，能有效抑制骨重吸收。我们前期构建的基于ALN的骨靶向胶束具有良好的骨肿瘤靶向性，然而大部分化疗药物被吸附在骨基质中，蓄积于转移瘤细胞内的药物较少，抑制溶骨性骨转移瘤生长和骨重吸收的作用不强。提示胶束到达骨病变部位后脱落ALN，解除骨基质对胶束的吸附，使化疗药物浓集于骨转移瘤细胞内，是提高胶束抗溶骨性骨转移瘤及抑制骨重吸收作用的关键。本研究分别以ALN和透明质酸（HA）为骨靶向和肿瘤细胞靶向材料，以酸响应和还原响应触发ALN和多西他赛逐次释放，构建骨转移瘤靶向壳交联胶束。深入探讨胶束的稳定性、环境响应性及体外靶向性，阐明胶束抗溶骨性骨转移瘤和抑制骨重吸收的作用，揭示作用机制，为研究骨转移瘤靶向递药系统提供新思路，为治疗溶骨性骨转移瘤提供新方法。

Osteolytic bone metastasis is a common complication in malignant cancer patients. There is a vicious circle between bone reabsorption and tumor growth in bone metastasis microenvironment, which leads to the refractory bone pain and pathological fracture. Chemotherapy drugs show low efficacy to osteolytic bone metastasis. Alendronate (ALN) has a strong affinity to the bone matrix where is invaded by tumor and can inhibit the bone reabsorption effectively. By using ALN, the bone targeted micelle was prepared by us. The micelle showed obvious bone metastasis targeting effect. However, the animal experiment showed that most of the chemotherapy drug were adsorbed in the bone matrix, only little amount of drug accumulated in bone metastasis cells, which resulted in a low effect on inhibiting the bone metastasis growth and bone reabsorption. The above experiment imply when the micelles reach to bone metastasis, shed ALN from micelle, subsequently relieve micelle from the adsorption of bone matrix and increase the accumulation of chemotherapy drug in the bone metastasis cells are the key points to improve the efficacy of micelle. In this study, a new shell-crosslinked micelle will be prepared by using ALN and hyaluronic acid (HA) as bone and tumor cells targeting moiety respectively. ALN and docetaxel is released from miselle through acidic and reductive triggered mechanism successively. The stability, microenvironment response and target characteristics of micelle will be thoroughly studied. Besides, the efficacy of micelle on anti osteolytic bone metastasis and inhibition of bone reabsorption will be clarified. The mechanism of the effect will be further investigated. The study will give a new way for the research of bone metastasis targeted drug delivery system and provide a new method for the treatment of osteolytic bone metastasis.

近年来对原发性乳腺癌的治疗取得了较大的进步，明显延长了患者的生存时间，但同时也增加了乳腺癌患者发生骨转移的几率，大量研究表明超过60%的晚期乳腺癌患者会发生骨转移。溶骨性骨转移瘤是乳腺癌常见并发症，转移瘤生长使骨重吸收加剧，引起顽固性骨痛和病理性骨折，化疗效果不佳。阿仑膦酸钠（ALN）对骨基质有很强的亲和力，本研究分别以ALN和透明质酸（HA）为骨靶向和肿瘤细胞靶向材料，以酸响应和还原响应触发ALN和多西他赛（DTX）逐次释放，构建骨转移瘤靶向壳交联胶束。研究了胶束的稳定性、环境响应性、体外靶向性，以及胶束体外抗溶骨性骨转移瘤和抑制骨重吸收的作用。研究结果表明所构建的胶束对骨的亲和力高、稳定性好，胶束在酸性环境（骨重吸收环境pH4～5）中脱落 ALN，使胶束从骨基质中解吸附。胶束释放DTX呈现明显的pH和GSH依赖性。上述结果提示胶束具有骨转移瘤微环境响应性，可将ALN和DTX分别释放于骨重吸收环境和骨转移瘤细胞内。胶束可剂量依赖性地减少乳腺癌骨转移瘤3D模型中颅骨表面肿瘤细胞数和凹陷小窝数，说明胶束具有明显的体外抗溶骨性骨转移瘤作用和抑制骨重吸收作用。胶束可抑制破骨细胞成熟，减少乳腺癌骨转移瘤3D模型中颅骨表面破骨细胞数，提示胶束通过抑制破骨细胞活性发挥抗骨重吸收的作用。上述研究结果提示所构建的胶束可能通过双向抑制骨转移肿瘤细胞生长与骨重吸收之间的恶性循环，发挥对骨转移瘤的治疗作用。该研究为研究骨转移瘤靶向递药系统提供了新思路，为治疗溶骨性骨转移瘤探索了新方法。