靶向治疗乳腺癌ErbB2阳性细胞pRNA二聚体的设计及可行性研究

Breast cancer is the most common female malignancy with a high incidence and ErbB2-overexpressing is often associated with a poor prognosis.At present,the target of ErbB2 positive breast cancer research focused on the interference with ErbB2 signaling pathway.However，the poor efficacy and toxicity restrain their utilization.The end points of interference with ErbB2 signaling pathway are aggregated into the cell cycle progression.Cyclin B1 is the key factor in the core mechanisms of cell cycle and highly expressed in breast cancer.Some studies have shown that the absence of Cyclin B1 inhibits proliferation and induces apoptosis.In our present work,using ErbB2 as a cell maker and a small molecule pRNA as a carrier.We should build stability and unimmunogenicity dimer pRNA-CyclinB1siRNA/pRNA-aptErbB2.We expect this dimer will import CyclinB1siRNA to ErbB2 overexpressing breast cancer cells,silence CyclinB1 expression,inhibit cell cycle progression and induce apoptosis.Then,we observe the anti-tumor efficiency,metabolism,ditribution and toxicity of the dimer in cells and mice.Our proposal will provide a novel methed for breast cancer therapy.

ErbB2阳性的乳腺癌恶性程度高，易复发转移，疗效差。目前国内外临床及实验阶段靶向ErbB2阳性乳腺癌的药物主要集中于干扰ErbB2信号通路，但疗效均不佳。ErbB2信号传导通路下游为细胞周期运转。CyclinB1为细胞周期核心机制的关键因子，在乳腺癌细胞存在高表达。研究表明，CyclinB1表达缺失细胞走向凋亡。本项目将ErbB2作为乳腺癌细胞识别标志，以小分子pRNA为载体，构建稳定且无免疫原性二聚体pRNA-CyclinB1siRNA/pRNA-aptErbB2，该二聚体在特异性识别ErbB2阳性细胞的同时导入CyclinB1siRNA到该细胞内沉默Cyclin B1的表达，阻止细胞增殖及诱导凋亡，随之我们检测二聚体在细胞及小鼠体内的抗瘤效率、代谢、分布及毒性。为临床乳腺癌治疗提供新的思路并奠定实验基础。

ErbB2阳性的乳腺癌恶性程度高，易复发转移，疗效差。目前国内外临床及实验阶段靶向ErbB2阳性乳腺癌的药物主要集中于干扰ErbB2信号通路，但疗效均不佳。ErbB2信号传导通路下游为细胞周期运转。CyclinB1为细胞周期核心机制的关键因子，在乳腺癌细胞存在高表达。研究表明，CyclinB1表达缺失细胞走向凋亡。本项目将ErbB2作为乳腺癌细胞识别标志，以小分子pRNA为载体，构建稳定且无免疫原性二聚体pRNA-CyclinB1siRNA/pRNA-aptErbB2，该二聚体在特异性识别ErbB2阳性细胞的同时导入CyclinB1siRNA到该细胞内沉默Cyclin B1的表达，阻止细胞增殖及诱导凋亡，随之我们检测二聚体在细胞及小鼠体内的抗瘤效率、代谢、分布及毒性。为临床乳腺癌治疗提供新的思路并奠定实验基础。