Journal
BIOMATERIALS
Volume 188, Issue -, Pages 160-172Publisher
ELSEVIER SCI LTD
DOI: 10.1016/j.biomaterials.2018.10.019
Keywords
Triple negative breast cancer (TNBC); Metastasis; Cancer stem cell (CSC); beta-Catenin; Integrin alpha 5 (ITGA5); NCTD; Lipid-polymer hybrid (LPH) nanoparticle
Funding
- American Cancer Society [RGS-15-026-01-CSM]
- Elsa U. Pardee Foundation
- Shared Animal Imaging and Histology Resources of the University of Kentucky Markey Cancer Center [P30CA177558]
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Cancer stem cells (CSCs) play pivotal roles in cancer metastasis, and strategies targeting cancer sternness may greatly reduce cancer metastasis and improve patients' survival. The canonical Wnt/beta-catenin pathway plays critical roles in CSC generation and maintenance as well as in normal stem cells. Non-specifically suppressing the Wnt/beta-catenin pathway for cancer therapy could be deleterious to normal cells. To achieve specific beta-catenin attenuation in cancer cells, we report an integrin alpha]5 (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-catenin. These findings suggest that ITGA5-targeting nanoparticles may provide a facil and unique strategy of specially attenuating-catenin in vivo for treating metastatic TNBC.
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