转铁蛋白引导的智能纳米囊泡增强临床PLK1抑制剂对急性髓系白血病的靶向性和效力。

Transferrin-guided intelligent nanovesicles augment the targetability and potency of clinical PLK1 inhibitor to acute myeloid leukemia.

作者信息

Xia Yifeng, An Jingnan, Li Jiaying, Gu Wenxing, Zhang Yifan, Zhao Songsong, Zhao Cenzhu, Xu Yang, Li Bin, Zhong Zhiyuan, Meng Fenghua

机构信息

Biomedical Polymers Laboratory, College of Chemistry, Chemical Engineering and Materials Science, and State Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou, 215123, PR China.

College of Pharmaceutical Sciences, Soochow University, Suzhou, 215123, PR China.

出版信息

Bioact Mater. 2022 Sep 20;21:499-510. doi: 10.1016/j.bioactmat.2022.08.032. eCollection 2023 Mar.

DOI:10.1016/j.bioactmat.2022.08.032

PMID:36185744

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9494038/

Abstract

Acute myeloid leukemia (AML) remains a most lethal hematological malignancy, partly because of its slow development of targeted therapies compared with other cancers. PLK1 inhibitor, volasertib (Vol), is among the few molecular targeted drugs granted breakthrough therapy status for AML; however, its fast clearance and dose-limiting toxicity greatly restrain its clinical benefits. Here, we report that transferrin-guided polymersomes (TPs) markedly augment the targetability, potency and safety of Vol to AML. Vol-loaded TPs (TPVol) with 4% transferrin exhibited best cellular uptake, effective down-regulation of p-PLK1, p-PTEN and p-AKT and superior apoptotic activity to free Vol in MV-4-11 leukemic cells. Intravenous injection of TPVol gave 6-fold higher AUC than free Vol and notable accumulation in AML-residing bone marrow. The efficacy studies in orthotopic MV-4-11 leukemic model demonstrated that TPVol significantly reduced leukemic cell proportions in periphery blood, bone marrow, liver and spleen, effectively enhanced mouse survival rate, and impeded bone loss. This transferrin-guided nano-delivery of molecular targeted drugs appears to be an interesting strategy towards the development of novel treatments for AML.

摘要

急性髓系白血病（AML）仍然是一种极具致死性的血液系统恶性肿瘤，部分原因是与其他癌症相比，其靶向治疗的发展较为缓慢。PLK1抑制剂沃拉替尼（Vol）是少数被授予AML突破性治疗地位的分子靶向药物之一；然而，其快速清除和剂量限制性毒性极大地限制了其临床疗效。在此，我们报告转铁蛋白引导的聚合物囊泡（TPs）显著增强了Vol对AML的靶向性、效力和安全性。载有Vol的TPs（TPVol）中4%的转铁蛋白表现出最佳的细胞摄取能力，能有效下调MV-4-11白血病细胞中p-PLK1、p-PTEN和p-AKT的表达，并具有比游离Vol更强的凋亡活性。静脉注射TPVol的曲线下面积（AUC）比游离Vol高6倍，且在AML浸润的骨髓中有明显蓄积。原位MV-4-11白血病模型的疗效研究表明，TPVol显著降低了外周血、骨髓、肝脏和脾脏中的白血病细胞比例，有效提高了小鼠存活率，并阻止了骨质流失。这种转铁蛋白引导的分子靶向药物纳米递送似乎是一种开发AML新型治疗方法的有趣策略。