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

Yunfei Li, Yajuan Xiao, Hsuan Pei Lin, Derek Reichel, Younsoo Bae, Eun Y. Lee, Yiguo Jiang, Xuefei Huang, Chengfeng Yang, Zhishan Wang

Research output: Contribution to journalArticlepeer-review

48 Scopus citations

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.

Original languageEnglish
Pages (from-to)160-172
Number of pages13
JournalBiomaterials
Volume188
DOIs
StatePublished - Jan 2019

Bibliographical note

Funding Information:
We thank Dr. Justin Mobley of NMR Center at University of Kentucky for the assistance to the 1 H NMR characterization of Cy7.5-NCTD. This study was supported in part by a Research Scholar Grant ( RGS-15-026-01-CSM ) from the American Cancer Society to C.Y. and a research grant from Elsa U. Pardee Foundation to Z.W. This research was also supported by the Shared Animal Imaging and Histology Resources of the University of Kentucky Markey Cancer Center ( P30CA177558 ).

Publisher Copyright:
© 2018 Elsevier Ltd

Keywords

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

ASJC Scopus subject areas

  • Bioengineering
  • Ceramics and Composites
  • Biophysics
  • Biomaterials
  • Mechanics of Materials

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