Sgc-8靶向PLGA-PEG纳米载体联合导入阿糖胞苷和nucleostemin shRNA在难治/复发AML中的疗效及相关机制研究

Refractory/relapsed acute myeloid leukemia is usually occurred in elder patients and resistant to routine chemotherapies with complex heredity.our data indicated that nucleostemin (NS) expression can be detected in 86.72% of BM samples from newly-diagnosed AML patients;NS mRNA expression is positively correlated with blast percentages (%) and CD34, CD117 and CD123 antigen expression in BM samples; a significant difference in NS expression between poor-risk and better-risk and between poor-risk and intermediate-risk AML patients was found. Our data indicate that NS should be expressed in blasts and hematopoietic stem/progenitor cells and,thus, can be used as potential therapy target for eliminating MRD of AML patients. Cytorabine is one kind of important chemotherapy drugs against Refractory/relapsed AML,but its application dosage and curative effect were limited because of its severe toxicity. We aimed to prepare for NP loading Ara-c and NS shRNA targeted by specific binding of Sgc-8 to PTK7 expressed in AML cells, NP can be endocytosed into cells, and then Ara-c and NS shRNA will be released to play roles against leukemia. This project is aimed to improve complete remission of refractory/relapsed AML, which is helpful for longer disease-free survival time and higher disease-free survival rate.

难治/复发的AML是一组遗传特征复杂、多见于老年患者、常规化疗疗效不佳的白血病。前期结果表明：86.72%的初治AML患者表达nucleostemin (NS)，其表达与骨髓原始细胞（BMPC）比例及造血干/祖细胞表面抗原（CD34、CD117、CD123）水平呈正相关；预后不良AML组的NS表达明显高于中间预后或者预后良好组。由于NS广泛表达于AML的BMPC及造血干/祖细胞，可作为其潜在的治疗靶点，达到清除MRD的目的。阿糖胞苷（Ara-c）是难治/复发AML的重要化疗药物，而严重的毒副反应限制了应用剂量和疗效。本项目拟制备PLGA-PEG联合载入Ara-c和NS shRNA的NP，经Sgc-8与AML细胞表面的PTK7靶向性结合后进入胞内，释放Ara-c和NS shRNA发挥联合抗白血病效应。本项目的实施，有助于提高难治/复发AML的CR率，延长无病生存时间并提高无病生存率。

难治/复发的AML是一组遗传特征复杂、多发生于老年患者、常规化疗疗效不佳的白血病.本项目拟制备Sgc-8靶向、PLGA-PEG载入Ara-c和NS shRNA的NP，Sgc-8与AML细胞表面的PTK7发生配/受体结合，NP经受体介导的内吞进入胞内，释放Ara-c和NS shRNA发挥联合抗白血病效应;我们已成功合成Sgc-8-NP-NS shRNA-Ara-c复合物，且该复合物可以靶向作用于PTK7+细胞，NS shRNA和Ara-c具有协同作用，具有更强的抗白血病效应和更少的副作用；NS可能通过端粒调控抑或直接的DNA损伤修复来维持LSC的功能和干细胞特性，靶向导入NS-shRNA后能从源头上清除MRD从而达到根治白血病的目的。本项目的实施，有助于提高难治/复发AML的CR率，延长无病生存时间并提高无病生存率