盐诱导激酶2响应型多肽水凝胶的制备及其在卵巢癌腹腔灌注治疗中的应用

盐诱导激酶2(SIK2)是一种丝氨酸/苏氨酸蛋白激酶，在卵巢癌的发生发展中扮演着至关重要的作用，是一个治疗卵巢癌的新候选靶点。前期研究显示，HG-9-91-01是一种有效的、高度特异性的SIK2抑制剂，对卵巢癌细胞有较好的抑制作用。但HG-9-91-01存在体内代谢快、生物利用度低的特点，需要探寻一种更有利于其靶向肿瘤的运输和持续发挥药效的载药体系。本项目拟构建一种新型多肽水凝胶体系，不仅能高效稳定负载SIK2抑制剂HG-9-91-01，还能在卵巢癌组织过表达SIK2的作用下响应性缓释HG-9-91-01，从而实现对卵巢癌细胞的持续抑制。项目拟通过卵巢癌细胞和卵巢癌移植动物模型，在体内外水平研究该水凝胶对于卵巢癌细胞的抑制效果并阐明抑制机制，进一步评估其在小鼠卵巢癌模型中用于腹腔灌注治疗的效果。本项目在疾病微环境响应性智能多肽水凝胶的设计和制备上实现了创新，为卵巢癌的临床治疗提供新途径。

Salt inducible kinase 2 (SIK2) is a serine/threonine protein kinase that plays an important role in the development of ovarian cancer. SIK2 is expected to be a new candidate target for the treatment of ovarian cancer. Previous studies have shown that HG-9-91-01 is an effective and highly specific SIK2 inhibitor with a good inhibitory effect on ovarian cancer cells. However, HG-9-91-01 has the characteristics of fast metabolism and low bioavailability in vivo. So it is necessary to explore a drug loading system which is more conducive to the transportation of targeted tumors and the continuous use of its efficacy. This project aims to construct a new polypeptide hydrogel system, which can not only efficiently and stably load the SIK2 inhibitor HG-9-91-01, but also respond to the action of over-expression of SIK2 in ovarian cancer tissues， then slow-release HG-9-91-01, so as to achieve continuous inhibition of ovarian cancer cells. The project intends to study the inhibitory effect of the hydrogel on ovarian cancer cells and elucidate the inhibitory mechanism in vivo and in vitro through ovarian cancer cells and ovarian cancer xenografted models, and further evaluate the effect of the hydrogel on peritoneal perfusion therapy in mouse ovarian cancer model. This project has achieved innovation in the design and preparation of disease micro-environmental responsive intelligent polypeptide hydrogels, providing a new approach for the clinical treatment of ovarian cancer.