Promoting tumor penetration of nanoparticles for cancer stem cell therapy by TGF-β signaling pathway inhibition
2015; Elsevier BV; Volume: 82; Linguagem: Inglês
10.1016/j.biomaterials.2015.12.014
ISSN1878-5905
AutoresZu-Qi Zuo, Kaige Chen, Xiaoyuan Yu, Gui Zhao, Song Shen, Zhi‐Ting Cao, Ying‐Li Luo, Yucai Wang, Jun Wang,
Tópico(s)Cancer, Hypoxia, and Metabolism
ResumoCancer stem cells (CSCs), which hold a high capacity for self-renewal, play a central role in the development, metastasis, and recurrence of various malignancies. CSCs must be eradicated to cure instances of cancer; however, because they can reside far from tumor vessels, they are not easily targeted by drug agents carried by nanoparticle-based drug delivery systems. We herein demonstrate that promoting tumor penetration of nanoparticles by transforming growth factor β (TGF-β) signaling pathway inhibition facilitates CSC therapy. In our study, we observed that although nanoparticles carrying siRNA targeting the oncogene polo-like kinase 1 (Plk1) efficiently killed breast CSCs derived from MDA-MB-231 cells in vitro, this intervention enriched CSCs in the residual tumor tissue following systemic treatment. However, inhibition of the TGF-β signaling pathway with LY364947, an inhibitor of TGF-β type I receptor, promoted the penetration of nanoparticles in tumor tissue, significantly ameliorating the intratumoral distribution of nanoparticles in MDA-MB-231 xenografts and further leading to enhanced internalization of nanoparticles by CSCs. As a result, synergistic treatment with a nanoparticle drug delivery system and LY364947 inhibited tumor growth and reduced the proportion of CSCs in vivo. This study suggests that enhanced tumor penetration of drug-carrying nanoparticles can enhance CSCs clearance in vivo and consequently provide superior anti-tumor effects.
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