骨靶向钙磷复合脂质药物基因共递送系统治疗前列腺癌骨转移研究

Bone metastasis is the leading cause of death in prostate cancer patients, and there is a lack of effective treatment. Our team found that the shh gene silencing can sensitize the killing effect of docetaxel in PC-3 prostate cancer cell line, and alendronate-modified calcium phosphate/phospholipid nanoparticles could effectively target the subcutaneous xenografts of prostate cancer in nude mice. Therefore we proposed that interfere with prostate cancer bone metastases microenvironment Shh-IL6-RANKL signal network using siRNA/DTXL calcium phosphate/phospholipid targeted nanoparticles, could sensitize DTXL killing effect, inhibit the progression of metastasis, and in turn effectively treat prostate cancer bone metastasis. We firstly prepared a bone targeted calcium phosphate/phospholipid hybrid nanoparticle drug delivery system, which possessed good stability, good biocompatibility and sustained release effect. In vitro co-culture of prostate cancer cells, osteoblasts and osteoclasts to simulate bone metastases, we studied the in vitro therapy effect and relevant mechanism of co-delivery nanoparticle system of siRNA/DTXL towards prostate cancer cell. Moreover, nude mice model of prostate cancer bone metastases was established, and we analyzed in vivo targeting effect of this drug delivery system in this model, and therapeutic effect and related mechanisms of siRNA/DTXL drug delivery system was also studied. The study results may provide a new theoretical basis and method for the treatment of prostate cancer bone metastases.

前列腺癌骨转移是引起前列腺癌患者死亡的重要因素，目前缺乏有效的治疗方法。课题组发现沉默前列腺癌细胞系中shh基因能够增敏多西他赛的杀伤作用，且阿仑唑奈修饰的钙磷复合脂质纳米粒能够有效地靶向分布至前列腺癌皮下移植瘤。因此提出共载siRNA/多西他赛（docetaxel，DTXL）钙磷复合脂质靶向纳米粒通过干扰前列腺癌骨转移灶微环境Shh-IL6-RANKL信号网络，实现增敏DTXL杀伤作用，抑制转移灶进展，最终有效地治疗前列腺癌骨转移灶，初步研究显示该递送系统具有较好的理化性质。本项目拟进一步从分子-细胞水平系统研究药物基因共递送系统增敏化疗、治疗骨转移瘤的作用及可能机制，在前列腺癌骨转移瘤动物模型中评价递送系统的靶向性，并进一步验证药物基因共递送系统体内治疗作用。课题研究成果将为临床上治疗前列腺癌骨转移瘤提供更多选择，将为前列腺癌骨转移瘤的治疗提供新的理论依据。

前列腺癌骨转移是前列腺癌患者死亡的首要原因，骨微环境内肿瘤细胞与基质细胞通过SHH-RANKL-IL6信号网络相互作用促进骨转移进展。本项目结合SHH-RANKL-IL6信号网络促进骨转移的效应，成功构建了磷酸钙复合磷脂的靶向纳米载药系统，磷酸钙核心组装SHH siRNA，壳层磷脂包载多西他赛，此外载药系统面进行靶向基团阿仑唑奈修饰。该纳米系统能够高效地载药，生物相容性较好，且能够缓慢地释放药物；体外细胞实验表明该纳米载药系统能够有效地干扰SHH-RANKL-IL6网络，抑制细胞的侵袭和迁移；前列腺癌骨转移瘤模型实验表明，靶向载药纳米系统能够有效靶向骨转移灶，抑制骨转移瘤进展，减少骨破坏，增加骨密度和骨量，对骨转移瘤的治疗取得了较好的结果，该项目的实施为前列腺癌骨转移的治疗提供了思路。通过本项目实施，在国内外期刊上发表5篇论文，其中包括Cancer communications (1篇，IF=10.39)，Pharmacological Research (1篇, IF=7.65)，Drug Design Development and Therapy (1篇, IF=4.2)等，另外两篇正在投稿中，申请国家发明专利1项，协助培养硕士研究生2名，获得山东省卫生健康委员会授予的“齐鲁卫生与健康杰出青年人才”。