Heparanase-driven sequential released nanoparticles for ferroptosis and tumor microenvironment modulations synergism in breast cancer therapy.

Published on Jan 1, 2021in Biomaterials10.317
· DOI :10.1016/J.BIOMATERIALS.2020.120429
Jun Zhang2
Estimated H-index: 2
(SJTU: Shanghai Jiao Tong University),
Jun Zhang6
Estimated H-index: 6
(SJTU: Shanghai Jiao Tong University)
+ 7 AuthorsQi Shen18
Estimated H-index: 18
(SJTU: Shanghai Jiao Tong University)
Abstract The normal chemotherapy only induces the intracellular apoptosis pathway to promote primary tumor cells death, while not inhibit tumor metastasis. Herein, we proposed a kind of heparanase (HPSE)-driven sequential released nanoparticles, which modified with β-cyclodextrin (β-CD) grafted heparin (NLC/H(D + F + S) NPs) co-loading with doxorubicin (DOX), ferrocene (Fc), and TGF-β receptor inhibitor (SB431542). NLC/H(D + F + S) NPs successfully inhibited breast cancer metastasis by intracellular and extracellular hybrid mechanism. DOX and Fc loaded in NLC/H(D + F + S) NPs effectively enhanced intracellular ROS level to activate ferroptosis pathway, the enhanced ROS also induced the apoptosis pathway and decreased MMP-9 expression to synergize with ferroptosis for tumor therapy. In extracellular site, SB431542 was sequentially released by HPSE-driven, which blocked tumor metastasis by modulating tumor microenvironment, decreasing TAFs activation, and reducing the secretion of TGF-β. In addition, anti-tumor immune response induced by ferroptosis further strengthened the effect of tumor therapy. Finally, under the help of intracellular and extracellular mechanisms launched by NLC/H(D + F + S) NPs, the satisfactory anti-tumor metastasis effect was obtained in the in vivo anti-tumor assays. Therefore, NLC/H(D + F + S) NPs was a novel dosage regimen for breast cancer therapy through intracellular and extracellular mechanisms, in which ferroptosis induced by ROS played an important role.
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