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In vivo β-catenin attenuation by the integrin α5-targeting nano-delivery strategy suppresses triple negative breast cancer stemness and metastasis.
Biomaterials ( IF 12.8 ) Pub Date : 2018-10-18 , DOI: 10.1016/j.biomaterials.2018.10.019
Yunfei Li 1 , Yajuan Xiao 1 , Hsuan-Pei Lin 1 , Derek Reichel 2 , Younsoo Bae 2 , Eun Y Lee 3 , Yiguo Jiang 4 , Xuefei Huang 5 , Chengfeng Yang 1 , Zhishan Wang 1
Affiliation  

Cancer stem cells (CSCs) play pivotal roles in cancer metastasis, and strategies targeting cancer stemness may greatly reduce cancer metastasis and improve patients' survival. The canonical Wnt/β-catenin pathway plays critical roles in CSC generation and maintenance as well as in normal stem cells. Non-specifically suppressing the Wnt/β-catenin pathway for cancer therapy could be deleterious to normal cells. To achieve specific β-catenin attenuation in cancer cells, we report an integrin α5 (ITGA5)-targeting nanoparticle for treating metastatic triple negative breast cancer (TNBC). We found that ITGA5 is highly expressed in strongly migratory and invasive TNBC cells as well as their lung metastatic foci, which rationalizes active-targeted drug delivery to TNBC cells via ITGA5 ligands such as a commercialized ligand-RGD motif (Arg-Gly-Asp). We modified lipid-polymer hybrid (LPH) nanoparticle for TNBC-targeted delivery of diacidic norcantharidin (NCTD), a potent anti-cancer compound but with short half-life. Notably, in vivo imaging analysis showed that RGD-decorated LPH (RGD-LPH) accumulated more significantly and remained much longer than LPH in nude mouse orthotopic mammary TNBC tumor and lung metastatic tumor, which implicated the feasibility of ITGA5-targeting strategy for treating metastatic TNBC. Moreover, systemic administration of NCTD-loaded RGD-LPH (RGD-LPH-NCTD) reduced nude mouse orthotopic mammary TNBC tumor growth and metastasis more effectively than free NCTD and LPH-NCTD via down-regulating β-catenin. These findings suggest that ITGA5-targeting nanoparticles may provide a facil and unique strategy of specially attenuating β-catenin in vivo for treating metastatic TNBC.

中文翻译:

靶向整联蛋白α5的纳米传递策略在体内的β-catenin抑制作用可抑制三阴性乳腺癌的干性和转移。

癌症干细胞(CSC)在癌症转移中起关键作用,针对癌症干性的策略可能会大大减少癌症转移并提高患者的生存率。经典的Wnt /β-catenin途径在CSC的生成和维持以及正常干细胞中起着至关重要的作用。非特异性抑制用于癌症治疗的Wnt /β-catenin途径可能对正常细胞有害。为了实现癌细胞中特定的β-catenin减毒,我们报道了以整联蛋白α5(ITGA5)为靶标的纳米颗粒,用于治疗转移性三阴性乳腺癌(TNBC)。我们发现ITGA5在强烈迁移和侵袭性TNBC细胞及其肺转移灶中高表达,这使通过ITGA5配体(例如商业化的配体-RGD基序(Arg-Gly-Asp))向TNBC细胞的活性靶向药物合理化。我们修改了脂质聚合物杂化(LPH)纳米颗粒,用于TNBC靶向的二酸降冰片素(NCTD)的递送,这是一种有效的抗癌化合物,但半衰期短。值得注意的是,体内成像分析显示,RGD修饰的LPH(RGD-LPH)在裸鼠原位乳腺TNBC肿瘤和肺转移性肿瘤中比LPH积累更多,并且保持更长的时间,这暗示了ITGA5靶向治疗转移性策略的可行性。 TNBC。此外,通过下调β-catenin,全身施用NCTD的RGD-LPH(RGD-LPH-NCTD)可以比游离NCTD和LPH-NCTD更有效地减少裸鼠原位乳腺TNBC肿瘤的生长和转移。
更新日期:2018-10-18
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