CD44和CD123序贯靶向药物共递送系统构建及其抗白血病治疗作用研究

急性髓细胞白血病（AML）涉及上千种基因异常或突变，有限的基因靶向药物难以满足治疗需求，化疗一直是治疗的首选策略，但易产生严重的毒副作用。此外，由于AML细胞和白血病干细胞常藏身于骨髓中而难以被清除，导致高复发率和耐药。.CD123在AML细胞和白血病干细胞上高表达，但正常造血干细胞和内皮细胞也有低水平表达，导致CD123靶向药物研发遭遇瓶颈。本项目拟在前期研发的CD123化学合成拮抗多肽纳米胶束（mPO-6）基础上，建立层层递进的双靶药物递送系统，在AML细胞和难治性AML小鼠模型上研究其疗效与机制。利用透明质酸（HA）对不同类型细胞CD44的差异性结合，特异性识别高表达CD44的AML细胞和白血病干细胞。同时，将阿霉素（Dox）组装到mPO-6中并“隐藏”于HA壳中，待HA识别靶细胞后，再将CD123靶向药物释放出来。该策略有望突破CD123靶向治疗的瓶颈，具有重要的临床转化应用价值。

Acute myeloid leukemia (AML) is a malignant heterogeneous hematological disease which involves thousands of mutations. There are too many challenges to develop the mutations-targeting therapies, so chemotherapy has always been the preferred AML treatment strategy, but it is easy to cause serious side effects. In addition, after being attacked by chemotherapeutic drugs, AML cells and leukemia stem cells are still remained in the bone marrow and difficult to eradicate, leading to the high recurrence rates and drug resistance of the AML patients..CD123 is highly expressed on the surface of multiple AML cells and leukemic stem cells, but low expressed in normal hematopoietic stem cells and endothelial cells, leading to a bottleneck in the development of CD123-targeted drugs. Based on the CD123 antagonistic peptide nanomicelles (mPO-6) developed previously, in this study, we intend to establish a progressive dual-targeting drug delivery system, and investigate its efficacy and mechanism in AML cells and refractory AML mouse model. Differential binding of CD44 to different cell types by hyaluronic acid (HA) is used to specifically identify AML cells and leukemia stem cells with high expression of CD44. The doxorubicin is assembled into mPO-6 and then "hidden" in the HA shell. After HA recognizes the target cells, the CD123-targeted drugs are released. This strategy is expected to break through the bottleneck of CD123 targeted therapy and shows an important clinical translational potential in AML therapy.