期刊
BIOMATERIALS
卷 152, 期 -, 页码 47-62出版社
ELSEVIER SCI LTD
DOI: 10.1016/j.biomaterials.2017.10.035
关键词
Multiplexed peptide conjugated; nanoparticle; Wnt/LRP receptors; uPAR; Cancer stem cells; Chemo-resistant breast cancer
资金
- NIH [R01CA154129A, R01CA154129A03S1]
- SBIR Phase II Contract [HHSN261201200029C]
- Sindab Pilot Grant on Biomarkers for Breast Cancer Stem Cells
- Brenda Nease Breast cancer Fund
- Nancy Panoz Chair funds
- NATIONAL CANCER INSTITUTE [R01CA095643, U01CA198913, R01CA154129] Funding Source: NIH RePORTER
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 levels 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 nano particle (IONP) drug carrier conjugated with peptides that are 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/beta-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. (C) 2017 Elsevier Ltd. All rights reserved.
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