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Research Article

Targeting cancer-associated fibroblasts with hydroxyethyl starch nanomedicine boosts cancer therapy

Chong Wang1,§, Huimin Wang1,§, Hai Yang1,2,§, Chen Xu1, Qiang Wang1, Zheng Li1, Zhijie Zhang1, Jiankun Guan1, Ximiao Yu3, Xiaoquan Yang3, Xiangliang Yang1,2,4,5,7, Zifu Li1,4,5,6,7()
National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, China
GBA Research Innovation Institute for Nanotechnology, Guangzhou 510530, China
Key Laboratory of Biomedical Photonics (HUST), Ministry of Education, Huazhong University of Science and Technology, Wuhan 430074, China
Key Laboratory of Molecular Biophysics of Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, China
Hubei Key Laboratory of Bioinorganic Chemistry and Materia Medical, Huazhong University of Science and Technology, Wuhan 430074, China
Hubei Engineering Research Center for Biomaterials and Medical Protective Materials, Huazhong University of Science and Technology, Wuhan 430074, China
Hubei Bioinformatics and Molecular Imaging Key Laboratory, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, China

§ Chong Wang, Huimin Wang, and Hai Yang contributed equally to this work.

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Graphical Abstract

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A cancer-associated fibroblasts (CAFs) targeting theranostic nanomedicine was prepared to reduce extracellular matrix (ECM) components by the combination of photothermal- and chemo-therapies, which decrease solid stress and mechanical stiffness of tumor tissues, normalize intratumoral blood vessels to promote the delivery of nanomedicine and oxygen, and eliminate cancer stem cells (CSCs) for potent antitumor effect.

Abstract

Cancer-associated fibroblasts (CAFs) play an important role in facilitating the progression of triple-negative breast cancer (TNBC) by deteriorating the tumor mechanical microenvironment (TMME). Herein, we designed a CAFs-targeting nanomedicine by conjugating doxorubicin (DOX)-loaded hydroxyethyl starch-IR780 nanoparticles (NPs) with Cys-Arg-Glu-Lys-Ala (CREKA) peptide, which had a special affinity for fibronectin overexpressed on CAFs. After systemic administration, the NPs efficiently targeted CAFs and generated hyperthermia upon light irradiation, decreasing CAFs through the combination of chemo- and photothermal-therapies. Thus, a series of changes in TMME were achieved by reducing CAFs, which further disrupted the niche of cancer stem cells (CSCs) to affect their survival. As a result, the tumor growth was significantly inhibited in 4T1 tumors. The strategy of TMME modulation and CSCs elimination through targeting and depleting CAFs provides a novel therapeutic treatment for desmoplastic solid tumors.

Keywords

hydroxyethyl starchcancer-associated fibroblaststumor mechanical microenvironmentcancer stem cellscombination therapy

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Nano Research
Volume 16 Issue 5,
May 2023
Pages 7323-7336
DOI: 10.1007/s12274-023-5394-7
Cite this article:
Wang C, Wang H, Yang H, et al. Targeting cancer-associated fibroblasts with hydroxyethyl starch nanomedicine boosts cancer therapy. Nano Research, 2023, 16(5): 7323-7336. https://doi.org/10.1007/s12274-023-5394-7
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