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Nano Research 2023, 16(5): 7323-7336 https://doi.org/10.1007/s12274-023-5394-7
Research Article | Issue | Published: 21 January 2023

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

Show Author's Information 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.

Keywords:
combination therapy, cancer stem cells, hydroxyethyl starch, cancer-associated fibroblasts, tumor mechanical microenvironment
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Nano biology
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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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Abstract Full text Electronic supplementary material About this article

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.


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Abstract
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Electronic supplementary material
About this article

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

Show Author's information 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.

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: combination therapy, cancer stem cells, hydroxyethyl starch, cancer-associated fibroblasts, tumor mechanical microenvironment

References(48)

[1]

Kalluri, R. The biology and function of fibroblasts in cancer. Nat. Rev. Cancer 2016, 16, 582–598.
DOI Google Scholar
[2]

Biffi, G.; Tuveson, D. A. Diversity and biology of cancer-associated fibroblasts. Physiol. Rev. 2021, 101, 147–176.
DOI Google Scholar
[3]

Hu, D. D.; Li, Z. Q.; Zheng, B.; Lin, X. X.; Pan, Y. H.; Gong, P. R.; Zhuo, W. Y.; Hu, Y. J.; Chen, C.; Chen, L. N. et al. Cancer-associated fibroblasts in breast cancer: Challenges and opportunities. Cancer. Commun. 2022, 42, 401–434.
DOI Google Scholar
[4]

Bulle, A.; Lim, K. H. Beyond just a tight fortress: Contribution of stroma to epithelial-mesenchymal transition in pancreatic cancer. Signal Transduct. Target. Ther. 2020, 5, 249.
DOI Google Scholar
[5]

Hyun, J.; Kim, H. W. Leveraging cellular mechano-responsiveness for cancer therapy. Trends Mol. Med. 2022, 28, 155–169.
DOI Google Scholar
[6]

Taddei, M. L.; Giannoni, E.; Comito, G.; Chiarugi, P. Microenvironment and tumor cell plasticity: An easy way out. Cancer Lett. 2013, 341, 80–96.
DOI Google Scholar
[7]

Nia, H. T.; Munn, L. L.; Jain, R. K. Physical traits of cancer. Science 2020, 370, eaaz0868.
DOI Google Scholar
[8]

Levental, K. R.; Yu, H. M.; Kass, L.; Lakins, J. N.; Egeblad, M.; Erler, J. T.; Fong, S. F. T.; Csiszar, K.; Giaccia, A.; Weninger, W. et al. Matrix crosslinking forces tumor progression by enhancing integrin signaling. Cell 2009, 139, 891–906.
DOI Google Scholar
[9]

Tse, J. M.; Cheng, G.; Tyrrell, J. A.; Wilcox-Adelman, S. A.; Boucher, Y.; Jain, R. K.; Munn, L. L. Mechanical compression drives cancer cells toward invasive phenotype. Proc. Natl. Acad. Sci. USA 2012, 109, 911–916.
DOI Google Scholar
[10]

Stylianopoulos, T.; Jain, R. K. Combining two strategies to improve perfusion and drug delivery in solid tumors. Proc. Natl. Acad. Sci. USA 2013, 110, 18632–18637.
DOI Google Scholar
[11]

Stylianopoulos, T.; Munn, L. L.; Jain, R. K. Reengineering the physical microenvironment of tumors to improve drug delivery and efficacy: From mathematical modeling to bench to bedside. Trends Cancer 2018, 4, 292–319.
DOI Google Scholar
[12]

Su, S. C.; Chen, J. N.; Yao, H. R.; Liu, J.; Yu, S. B.; Lao, L. Y.; Wang, M. H.; Luo, M. L.; Xing, Y.; Chen, F. et al. CD10+GPR77+ cancer-associated fibroblasts promote cancer formation and chemoresistance by sustaining cancer stemness. Cell 2018, 172, 841–856.e16.
DOI Google Scholar
[13]

Heddleston, J. M.; Li, Z.; Lathia, J. D.; Bao, S.; Hjelmeland, A. B.; Rich, J. N. Hypoxia inducible factors in cancer stem cells. Br. J. Cancer 2010, 102, 789–795.
DOI Google Scholar
[14]

De Andrés, J. L.; Griñán-Lisón, C.; Jiménez, G.; Marchal, J. A. Cancer stem cell secretome in the tumor microenvironment: A key point for an effective personalized cancer treatment. J. Hematol. Oncol. 2020, 13, 136.
DOI Google Scholar
[15]

Saygin, C.; Matei, D.; Majeti, R.; Reizes, O.; Lathia, J. D. Targeting cancer stemness in the clinic: From hype to hope. Cell Stem Cell 2019, 24, 25–40.
DOI Google Scholar
[16]

Clara, J. A.; Monge, C.; Yang, Y. Z.; Takebe, N. Targeting signalling pathways and the immune microenvironment of cancer stem cells—A clinical update. Nat. Rev. Clin. Oncol. 2020, 17, 204–232.
DOI Google Scholar
[17]

Yang, L. Q.; Shi, P. F.; Zhao, G. C.; Xu, J.; Peng, W.; Zhang, J. Y.; Zhang, G. H.; Wang, X. W.; Dong, Z.; Chen, F. et al. Targeting cancer stem cell pathways for cancer therapy. Signal Transduct. Target. Ther. 2020, 5, 8.
DOI Google Scholar
[18]

Wu, F. L.; Yang, J.; Liu, J. J.; Wang, Y.; Mu, J. T.; Zeng, Q. X.; Deng, S. Z.; Zhou, H. M. Signaling pathways in cancer-associated fibroblasts and targeted therapy for cancer. Signal Transduct. Target. Ther. 2021, 6, 218.
DOI Google Scholar
[19]

Chen, J. T.; Ding, Z. Y.; Li, S.; Liu, S.; Xiao, C.; Li, Z. F.; Zhang, B. X.; Chen, X. P.; Yang, X. L. Targeting transforming growth factor-β signaling for enhanced cancer chemotherapy. Theranostics 2021, 11, 1345–1363.
DOI Google Scholar
[20]

Froeling, F. E. M.; Feig, C.; Chelala, C.; Dobson, R.; Mein, C. E.; Tuveson, D. A.; Clevers, H.; Hart, I. R.; Kocher, H. M. Retinoic acid-induced pancreatic stellate cell quiescence reduces paracrine Wnt-β-catenin signaling to slow tumor progression. Gastroenterology 2011, 141, 1486–1497.e14.
DOI Google Scholar
[21]

Wang, L. Y.; Liu, Z. M.; Zhou, Q.; Gu, S. F.; Liu, X. S.; Huang, J. X.; Jiang, H. P.; Wang, H. F.; Cao, L. P.; Sun, J. H. et al. Prodrug nanoparticles rationally integrating stroma modification and chemotherapy to treat metastatic pancreatic cancer. Biomaterials 2021, 278, 121176.
DOI Google Scholar
[22]

Zhou, S. Y.; Zhen, Z. P.; Paschall, A. V.; Xue, L. J.; Yang, X. Y.; Blackwell, A. G. B.; Cao, Z. W.; Zhang, W. Z.; Wang, M. Z.; Teng, Y. et al. FAP-targeted photodynamic therapy mediated by ferritin nanoparticles elicits an immune response against cancer cells and cancer associated fibroblasts. Adv. Funct. Mater. 2021, 31, 2007017.
DOI Google Scholar
[23]

Feng, J. X.; Xu, M. J.; Wang, J. H.; Zhou, S. L.; Liu, Y. P.; Liu, S. S.; Huang, Y. K.; Chen, Y.; Chen, L.; Song, Q. X. et al. Sequential delivery of nanoformulated α-mangostin and triptolide overcomes permeation obstacles and improves therapeutic effects in pancreatic cancer. Biomaterials 2020, 241, 119907.
DOI Google Scholar
[24]

Wu, H. L.; Hu, H.; Wan, J. L.; Li, Y. M.; Wu, Y. X.; Tang, Y. X.; Xiao, C.; Xu, H. B.; Yang, X. L.; Li, Z. F. Hydroxyethyl starch stabilized polydopamine nanoparticles for cancer chemotherapy. Chem. Eng. J. 2018, 349, 129–145.
DOI Google Scholar
[25]

Xiong, Y. X.; Wang, Z. B.; Wang, Q.; Deng, Q. Y.; Chen, J. T.; Wei, J. S.; Yang, X. Q.; Yang, X. L.; Li, Z. F. Tumor-specific activatable biopolymer nanoparticles stabilized by hydroxyethyl starch prodrug for self-amplified cooperative cancer therapy. Theranostics 2022, 12, 944–962.
DOI Google Scholar
[26]

Wang, H. M.; Hu, H.; Yang, H.; Li, Z. F. Hydroxyethyl starch based smart nanomedicine. RSC Adv. 2021, 11, 3226–3240.
DOI Google Scholar
[27]

Xiao, C.; Hu, H.; Yang, H.; Li, S.; Zhou, H.; Ruan, J.; Zhu, Y. T.; Yang, X. L.; Li, Z. F. Colloidal hydroxyethyl starch for tumor-targeted platinum delivery. Nanoscale Adv. 2019, 1, 1002–1012.
DOI Google Scholar
[28]

Zhou, Q.; Li, Y. H.; Zhu, Y. H.; Yu, C.; Jia, H. B.; Bao, B. H.; Hu, H.; Xiao, C.; Zhang, J. Q.; Zeng, X. F. et al. Co-delivery nanoparticle to overcome metastasis promoted by insufficient chemotherapy. J. Control. Release 2018, 275, 67–77.
DOI Google Scholar
[29]

Hu, H.; Li, Y. H.; Zhou, Q.; Ao, Y. X.; Yu, C.; Wan, Y.; Xu, H. B.; Li, Z. F.; Yang, X. L. Redox-sensitive hydroxyethyl starch-doxorubicin conjugate for tumor targeted drug delivery. ACS Appl. Mater. Interfaces 2016, 8, 30833–30844.
DOI Google Scholar
[30]

Luo, Q.; Wang, P. X.; Miao, Y. Q.; He, H. B.; Tang, X. A novel 5-fluorouracil prodrug using hydroxyethyl starch as a macromolecular carrier for sustained release. Carbohydr. Polym. 2012, 87, 2642–2647.
DOI Google Scholar
[31]

Hu, H.; Wan, J. L.; Huang, X. T.; Tang, Y. X.; Xiao, C.; Xu, H. B.; Yang, X. L.; Li, Z. F. iRGD-decorated reduction-responsive nanoclusters for targeted drug delivery. Nanoscale 2018, 10, 10514–10527.
DOI Google Scholar
[32]

Zhai, Y. H.; Liu, M.; Yang, T.; Luo, J.; Wei, C. G.; Shen, J. K.; Song, X.; Ke, H. T.; Sun, P.; Guo, M. et al. Self-activated arsenic manganite nanohybrids for visible and synergistic thermo/immuno-arsenotherapy. J. Control. Release 2022, 350, 761–776.
DOI Google Scholar
[33]

Iqbal, H.; Yang, T.; Li, T.; Zhang, M. Y.; Ke, H. T.; Ding, D. W.; Deng, Y. B.; Chen, H. B. Serum protein-based nanoparticles for cancer diagnosis and treatment. J. Control. Release 2021, 329, 997–1022.
DOI Google Scholar
[34]

Li, Y. H.; Wu, Y. X.; Chen, J. T.; Wan, J. L.; Xiao, C.; Guan, J. K.; Song, X. L.; Li, S. Y.; Zhang, M. M.; Cui, H. C. et al. A simple glutathione-responsive turn-on theranostic nanoparticle for dual-modal imaging and chemo-photothermal combination therapy. Nano Lett. 2019, 19, 5806–5817.
DOI Google Scholar
[35]

Wang, X. X.; Ye, N. B.; Xu, C.; Xiao, C.; Zhang, Z. J.; Deng, Q. Y.; Li, S. Y.; Li, J. Y.; Li, Z. F.; Yang, X. L. Hyperbaric oxygen regulates tumor mechanics and augments abraxane and gemcitabine antitumor effects against pancreatic ductal adenocarcinoma by inhibiting cancer-associated fibroblasts. Nano Today 2022, 44, 101458.
DOI Google Scholar
[36]

Liu, X.; Ye, N. B.; Xiao, C.; Wang, X. X.; Li, S. Y.; Deng, Y. H.; Yang, X. Q.; Li, Z. F.; Yang, X. L. Hyperbaric oxygen regulates tumor microenvironment and boosts commercialized nanomedicine delivery for potent eradication of cancer stem-like cells. Nano Today 2021, 40, 101248.
DOI Google Scholar
[37]

Zhao, Y.; Xie, R. S.; Yodsanit, N.; Ye, M. Z.; Wang, Y. Y.; Gong, S. Q. Biomimetic fibrin-targeted and H2O2-responsive nanocarriers for thrombus therapy. Nano Today 2020, 35, 100986.
DOI Google Scholar
[38]

Gong, Z. R.; Chen, M.; Ren, Q. S.; Yue, X. L.; Dai, Z. F. Fibronectin-targeted dual-acting micelles for combination therapy of metastatic breast cancer. Signal Transduct. Target. Ther. 2020, 5, 12.
DOI Google Scholar
[39]

Zhang, Z. J.; Deng, Q. Y.; Xiao, C.; Li, Z. F.; Yang, X. L. Rational design of nanotherapeutics based on the five features principle for potent elimination of cancer stem cells. Acc. Chem. Res. 2022, 55, 526–536.
DOI Google Scholar
[40]

Li, R.; Li, Y. P.; Zhang, J. H.; Liu, Q. H.; Wu, T.; Zhou, J.; Huang, H.; Tang, Q.; Huang, C. Y.; Huang, Y. et al. Targeted delivery of celastrol to renal interstitial myofibroblasts using fibronectin-binding liposomes attenuates renal fibrosis and reduces systemic toxicity. J. Control. Release 2020, 320, 32–44.
DOI Google Scholar
[41]

Chen, X. M.; Song, E. W. Turning foes to friends: Targeting cancer-associated fibroblasts. Nat. Rev. Drug Discov. 2019, 18, 99–115.
DOI Google Scholar
[42]

Jain, R. K.; Martin, J. D.; Stylianopoulos, T. The role of mechanical forces in tumor growth and therapy. Annu. Rev. Biomed. Eng. 2014, 16, 321–346.
DOI Google Scholar
[43]

Nia, H. T.; Liu, H.; Seano, G.; Datta, M.; Jones, D.; Rahbari, N.; Incio, J.; Chauhan, V. P.; Jung, K.; Martin, J. D. et al. Solid stress and elastic energy as measures of tumour mechanopathology. Nat. Biomed. Eng. 2017, 1, 0004.
DOI Google Scholar
[44]

Mpekris, F.; Voutouri, C.; Baish, J. W.; Duda, D. G.; Munn, L. L.; Stylianopoulos, T.; Jain, R. K. Combining microenvironment normalization strategies to improve cancer immunotherapy. Proc. Natl. Acad. Sci. USA 2020, 117, 3728–3737.
DOI Google Scholar
[45]

Visvader, J. E.; Lindeman, G. J. Cancer stem cells: Current status and evolving complexities. Cell Stem Cell 2012, 10, 717–728.
DOI Google Scholar
[46]

Hurtado, P.; Martínez-Pena, I.; Piñeiro, R. Dangerous liaisons: Circulating tumor cells (CTCs) and cancer-associated fibroblasts (CAFs). Cancers (Basel) 2020, 12, 2861.
DOI Google Scholar
[47]

Plaks, V.; Kong, N.; Werb, Z. The cancer stem cell niche: How essential is the niche in regulating stemness of tumor cells? Cell Stem Cell 2015, 16, 225–238.
DOI Google Scholar
[48]

Khan, I. N.; Ullah, N.; Hussein, D.; Saini, K. S. Current and emerging biomarkers in tumors of the central nervous system: Possible diagnostic, prognostic and therapeutic applications. Semin. Cancer Biol. 2018, 52, 85–102.
DOI Google Scholar
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Publication history
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Acknowledgements

Publication history

Received: 24 October 2022
Revised: 05 December 2022
Accepted: 08 December 2022
Published: 21 January 2023
Issue date: May 2023

Copyright

© Tsinghua University Press 2023

Acknowledgements

Acknowledgements

We thank the Research Core Facilities for Life Science (HUST), the Optical Bioimaging Core Facility of WNLO-HUST, and the Analytical and Testing Center of HUST for the facility support. This work was financially supported by grants from the National Research and Development Program of China (Nos. 2018YFA0208900, 2020YFA0211200, and 2020YFA0710700), the National Natural Science Foundation of China (Nos. 82172757 and 31972927), the Scientific Research Foundation of Huazhong University of Science and Technology (No. 3004170130), the Program for HUST Academic Frontier Youth Team (No. 2018QYTD01), and the HCP Program for HUST.

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