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Author Notes:

Address Correspondence to: Dr. Lily Yang, Department of Surgery, Emory University School of Medicine,1365-C Clifton Road, NE, Atlanta, GA, 30322, USA. Tel: + 1 404-778-4269, Fax: + 1 404-778-5530, lyang02@emory.edu.

We thank Dr. Malgorzata Lipowska for synthesis of NIR 830 dye and Rachel Commander for assisting in the graphical abstract.

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Research Funding:

This research project was supported by the following NIH grants: R01CA154129A and R01CA154129A03S1 (Yang), SBIR Phase II Contract NO. HHSN261201200029C (Wang and Yang), Sindab Pilot Grant on Biomarkers for Breast Cancer Stem Cells, Brenda Nease Breast cancer Fund (Yang, Winship Gala Scholar Award), and Nancy Panoz Chair funds (Yang).

Keywords:

  • Science & Technology
  • Technology
  • Engineering, Biomedical
  • Materials Science, Biomaterials
  • Engineering
  • Materials Science
  • Multiplexed peptide conjugated
  • nanoparticle
  • Wnt/LRP receptors
  • uPAR
  • Cancer stem cells
  • Chemo-resistant breast cancer
  • EPITHELIAL-MESENCHYMAL TRANSITION
  • E-CADHERIN EXPRESSION
  • SELF-RENEWAL
  • IN-VIVO
  • METASTASIS
  • THERAPY
  • PROLIFERATION
  • CHEMOTHERAPY
  • SURVIVAL

Dual-targeting Wnt and uPA receptors using peptide conjugated ultra-small nanoparticle drug carriers inhibited cancer stem-cell phenotype in chemo-resistant breast cancer

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Journal Title:

Biomaterials

Volume:

Volume 152

Publisher:

, Pages 47-62

Type of Work:

Article | Post-print: After Peer Review

Abstract:

Heterogeneous tumor cells, high incidence of tumor recurrence, and decrease in overall survival are the major challenges for the treatment of chemo-resistant breast cancer. Results of our study showed differential chemotherapeutic responses among breast cancer patient derived xenograft (PDX) tumors established from the same patients. All doxorubicin(Dox)-resistant tumors expressed higher level of cancer stem-like cell biomarkers, including CD44, Wnt and its receptor LRP5/6, relative to Dox-sensitive tumors. To effectively treat resistant tumors, we developed an ultra-small magnetic iron oxide nanoparticle (IONP) drug carrier conjugated with peptides that dually targeted to Wnt/LRP5/6 and urokinase plasminogen activator receptor (uPAR). Our results showed that simultaneous binding to LRP5/6 and uPAR by the dual receptor targeted IONPs was required to inhibit breast cancer cell invasion. Molecular analysis revealed that the dual receptor targeted IONPs significantly inhibited Wnt/β-catenin signaling and cancer stem-like phenotype of tumor cells, with marked reduction of Wnt ligand, CD44 and uPAR. Systemic administration of the dual targeted IONPs led to nanoparticle-drug delivery into PDX tumors, resulting in stronger tumor growth inhibition compared to non-targeted or single-targeted IONP-Dox in a human breast cancer PDX model. Therefore, co-targeting Wnt/LRP and uPAR using IONP drug carriers is a promising therapeutic approach for effective drug delivery to chemo-resistant breast cancer.

Copyright information:

© 2017

This is an Open Access work distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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