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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.

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.

journal_name

Biomaterials

journal_title

Biomaterials

authors

Li Y,Xiao Y,Lin HP,Reichel D,Bae Y,Lee EY,Jiang Y,Huang X,Yang C,Wang Z

doi

10.1016/j.biomaterials.2018.10.019

subject

Has Abstract

pub_date

2019-01-01 00:00:00

pages

160-172

eissn

0142-9612

issn

1878-5905

pii

S0142-9612(18)30733-6

journal_volume

188

pub_type

杂志文章

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