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Biomaterials. 2019 Jan;188:160-172. doi: 10.1016/j.biomaterials.2018.10.019. Epub 2018 Oct 18.

In vivo β-catenin attenuation by the integrin α5-targeting nano-delivery strategy suppresses triple negative breast cancer stemness and metastasis.

Author information

1
Department of Toxicology and Cancer Biology, and Center for Research on Environment Disease, College of Medicine, University of Kentucky, Lexington, KY 40536, United States.
2
Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536, United States.
3
Department of Pathology and Laboratory Medicine, College of Medicine, University of Kentucky, Lexington, KY 40536, United States.
4
Institute for Chemical Carcinogenesis, State Key Laboratory of Respiratory Diseases, Guangzhou Medical University, Guangzhou, Guangdong, People's Republic of China.
5
Departments of Chemistry and Biomedical Engineering, Institute for Quantitative Health Science and Engineering, Michigan State University, East Lansing, MI 48824, United States.
6
Department of Toxicology and Cancer Biology, and Center for Research on Environment Disease, College of Medicine, University of Kentucky, Lexington, KY 40536, United States. Electronic address: chengfeng.yang@uky.edu.
7
Department of Toxicology and Cancer Biology, and Center for Research on Environment Disease, College of Medicine, University of Kentucky, Lexington, KY 40536, United States. Electronic address: zhishan.wang@uky.edu.

Abstract

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.

KEYWORDS:

Cancer stem cell (CSC); Integrin α5 (ITGA5); Lipid-polymer hybrid (LPH) nanoparticle; Metastasis; NCTD; Triple negative breast cancer (TNBC); β-Catenin

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