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Cited by 227Ferroptosis and cancer prognosisNanoparticle-Based Drug DeliveryNanoplatforms for cancer theranostics

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Simvastatin induced ferroptosis for triple-negative breast cancer therapy

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Yao, Xianxian, Xie, Ruihong, Cao, Yongbin, Tang, Jing, Men, Yongzhi, Peng, Haibao, Yang, Wuli·2021·Journal of Nanobiotechnology
DOI 10.1186/s12951-021-01058-1PMC PMC8502296
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Abstract

Triple-negative breast cancer (TNBC), a management of aggressive breast cancer, remains an unmet medical challenge. Although a wave of efforts had spurred to design novel therapeutic method of TNBC, unpredictable prognosis with lacking effective therapeutic targets along with the resistance to apoptosis seriously limited survival benefits. Ferroptosis is a non-apoptotic form of cell death that is induced by excessive lipid peroxidation, which provide an innovative way to combat cancer. Emerging evidence suggests that ferroptosis plays an important role in the treatment of TNBC cells. Herein, a novel ferroptosis nanomedicine was prepared by loading simvastatin (SIM), a ferroptosis drug, into zwitterionic polymer coated magnetic nanoparticles (Fe 3 O 4 @PCBMA) to improve the therapeutic effect of TNBC. The as-obtained Fe 3 O 4 @PCBMA-SIM nanoparticles demonstrated more cytotoxicity against MDA-MB-231 than MCF-7 due to the higher expression of 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR), which demonstrated that statins could effectively kill TNBC. Further experiments showed that SIM could inhibit the expression of HMGCR to downregulate the mevalonate (MVA) pathway and glutathione peroxidase 4 (GPX4), thereby inducing cancer cell ferroptosis. What’s more, PCBMA endows Fe 3 O 4 @PCBMA longer blood circulation performance to enhance their accumulation at tumor sites. Given that Fe 3 O 4 have proven for clinical applications by the U.S. Food and Drug Administration (FDA) and SIM could induce cancer cell ferroptosis, the developed Fe 3 O 4 @PCBMA-SIM nanosystem would have great potential in clinics for overcoming the drug resistance brought about by apoptotic drugs to cancer cells.

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Scheme 1 Schematic illustration of multifunctional nanoplatform for ferroptosis
Scheme 1 Schematic illustration of multifunctional nanoplatform for ferroptosisCC BY · PubMed Central
Fig. 1 TEM images of Fe3O4 (A) and Fe3O4@PCBMA (B) nanoparticles; SEM images of Fe3O4 (C) and Fe3O4@PCBMA nanoparticles (D); DLS diameters of Fe3O4, Fe3O4@PCBMA, and Fe3O4@PCBMA-SIM nanoparticles (E); Zeta potential of Fe3O4, Fe3O4@PCBMA, and Fe3O4@PCBMA-SIM nanoparticles (F); TGA analysis of Fe3O4, Fe3O4@PCBMA, SIM, Fe3O4-SIM and Fe3O4@PCBMA-SIM nanoparticles measured in air (G); FT-IR spectra of Fe3O4, Fe3O4@PCBMA, SIM, Fe3O4-SIM and Fe3O4@PCBMA-SIM nanoparticles (H); UV–vis spectra of SIM, Fe3O4-SIM, Fe3O4@PCBMA-SIM, Fe3O4 and Fe3O4@PCBMA nanoparticles (I)
Fig. 1 TEM images of Fe3O4 (A) and Fe3O4@PCBMA (B) nanoparticles; SEM images of Fe3O4 (C) and Fe3O4@PCBMA nanoparticles (D); DLS diameters of Fe3O4, Fe3O4@PCBMA, and Fe3O4@PCBMA-SIM nanoparticles (E); Zeta potential of Fe3O4, Fe3O4@PCBMA, and Fe3O4@PCBMA-SIM nanoparticles (F); TGA analysis of Fe3O4, Fe3O4@PCBMA, SIM, Fe3O4-SIM and Fe3O4@PCBMA-SIM nanoparticles measured in air (G); FT-IR spectra of Fe3O4, Fe3O4@PCBMA, SIM, Fe3O4-SIM and Fe3O4@PCBMA-SIM nanoparticles (H); UV–vis spectra of SIM, Fe3O4-SIM, Fe3O4@PCBMA-SIM, Fe3O4 and Fe3O4@PCBMA nanoparticles (I)CC BY · PubMed Central
Fig. 2 Schematic illustration of Fe3O4@PCBMA-SIM nanoparticles killing cancer cells (A); The degradation property of Fe3O4@PCBMA nanoparticles dispersed in different concentrations of GSH (0 mM and 10 mM) and pH values (5.0, 6.5 and 7.4) (B); Cumulative SIM releasing from Fe3O4-SIM and Fe3O4@PCBMA-SIM nanoparticles dispersed in 10 mM GSH (C); Cell viability of the MCF-7 (D) and MDA-MB-231 (E) cells after 48 h incubation with Fe3O4, Fe3O4@PCBMA, SIM, Fe3O4-SIM and Fe3O4@PCBMA-SIM suspensions; CLSM of control, Fe3O4@PCBMA, free SIM, Fe3O4-SIM and Fe3O4@PCBMA-SIM nanoparticles after uptake by MCF-7 and MDA-MB-231 cells (F)
Fig. 2 Schematic illustration of Fe3O4@PCBMA-SIM nanoparticles killing cancer cells (A); The degradation property of Fe3O4@PCBMA nanoparticles dispersed in different concentrations of GSH (0 mM and 10 mM) and pH values (5.0, 6.5 and 7.4) (B); Cumulative SIM releasing from Fe3O4-SIM and Fe3O4@PCBMA-SIM nanoparticles dispersed in 10 mM GSH (C); Cell viability of the MCF-7 (D) and MDA-MB-231 (E) cells after 48 h incubation with Fe3O4, Fe3O4@PCBMA, SIM, Fe3O4-SIM and Fe3O4@PCBMA-SIM suspensions; CLSM of control, Fe3O4@PCBMA, free SIM, Fe3O4-SIM and Fe3O4@PCBMA-SIM nanoparticles after uptake by MCF-7 and MDA-MB-231 cells (F)CC BY · PubMed Central
Fig. 3 CLSM (A) and flow cytometry analysis (B, C) of reactive oxygen species (ROS) generation in MCF-7 and MDA-MB-231 cells
Fig. 3 CLSM (A) and flow cytometry analysis (B, C) of reactive oxygen species (ROS) generation in MCF-7 and MDA-MB-231 cellsCC BY · PubMed Central
Fig. 4 Schematic illustration of ferroptosis mechanism (A); The GPX4 and HMGCR protein expression of MCF-7 cells after treated with Fe3O4@PCBMA, SIM, Fe3O4-SIM and Fe3O4@PCBMA-SIM (B, D, E); The GPX4 and HMGCR protein expression of MDA-MB-231 cells after treatment with Fe3O4@PCBMA, SIM, Fe3O4-SIM and Fe3O4@PCBMA-SIM (C, F, G); The HMGCR protein expression of MCF-7 cells and MDA-MB-231 cells and the corresponding intensity (H); Flow cytometry analysis of lipid hydroperoxides (LPO) generation in MCF-7 (I) and MDA-MB-231 cells (J)
Fig. 4 Schematic illustration of ferroptosis mechanism (A); The GPX4 and HMGCR protein expression of MCF-7 cells after treated with Fe3O4@PCBMA, SIM, Fe3O4-SIM and Fe3O4@PCBMA-SIM (B, D, E); The GPX4 and HMGCR protein expression of MDA-MB-231 cells after treatment with Fe3O4@PCBMA, SIM, Fe3O4-SIM and Fe3O4@PCBMA-SIM (C, F, G); The HMGCR protein expression of MCF-7 cells and MDA-MB-231 cells and the corresponding intensity (H); Flow cytometry analysis of lipid hydroperoxides (LPO) generation in MCF-7 (I) and MDA-MB-231 cells (J)CC BY · PubMed Central
Fig. 5 Biodistribution of Fe3O4 and Fe3O4 @PCBMA nanoparticles after 24 h injection (A); In vivo blood retention profiles of Fe3O4 and Fe3O4@PCBMA nanoparticles (1 mg/mL, 100 μL) (B); Tumor growth curves and body weight changes of nanomedicine. Treatments were performed on day 0, 3, 6 and 9. Error bars indicate the SD (n = 5) (C, D); Photographs (left) and weights (right) of tumors after therapy (E) *P < 0.05 **P < 0.01 ***P < 0.001
Fig. 5 Biodistribution of Fe3O4 and Fe3O4 @PCBMA nanoparticles after 24 h injection (A); In vivo blood retention profiles of Fe3O4 and Fe3O4@PCBMA nanoparticles (1 mg/mL, 100 μL) (B); Tumor growth curves and body weight changes of nanomedicine. Treatments were performed on day 0, 3, 6 and 9. Error bars indicate the SD (n = 5) (C, D); Photographs (left) and weights (right) of tumors after therapy (E) *P < 0.05 **P < 0.01 ***P < 0.001CC BY · PubMed Central
Fig. 6 Blood biochemistry indices of renal and hepatic function including alkaline phosphatase (ALP), alanine aminotransferase (ALT), aspartate aminotransferase (AST) (A); globulin (GLOB), total protein (TP), albumin (ALB) (B) and creatinine (CREA), cholesterol (CHOL), UREA (C); H&E-stained slices of liver spleen, heart, lung, and kidney from each group (D), Scale bars were 50 μm
Fig. 6 Blood biochemistry indices of renal and hepatic function including alkaline phosphatase (ALP), alanine aminotransferase (ALT), aspartate aminotransferase (AST) (A); globulin (GLOB), total protein (TP), albumin (ALB) (B) and creatinine (CREA), cholesterol (CHOL), UREA (C); H&E-stained slices of liver spleen, heart, lung, and kidney from each group (D), Scale bars were 50 μmCC BY · PubMed Central

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Metadata

Authors
Yao, X., Xie, R., Cao, Y., Tang, J., Men, Y., Peng, H., & Yang, W.
Affiliations
  • Fudan University (CN)
  • Stanford University (US)
  • Shanghai Jiao Tong University (CN)
Corresponding author
  • Peng, Haibao
  • Yang, Wuli
ORCID
Venue
Journal of Nanobiotechnology
Publisher
Springer Science and Business Media LLC
Published
2021-10-09
Volume
19
Issue
1
Pages
311-311
ISSN
1477-3155 (ISSN-L)
DOI
10.1186/s12951-021-01058-1
PMC
PMC8502296
OpenAlex
W3206510813
Cited by
227
References
41
Citations by year
2026: 27 · 2025: 67 · 2024: 59 · 2023: 44 · 2022: 29 · 2021: 1
FWCI
21.75
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Nanobiotechnology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • national natural science foundation of china (Grant Nos. 51933002, 51873041, 81902756)
  • program of shanghai academic research leader (20XD1400400)
  • the open project of state key laboratory of molecular engineering of polymers (No. K2021-19)
  • shanghai sailing program (No.19Y1439900)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Ferroptosis and cancer prognosis
  • Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
  • Physical Sciences › Engineering › Biomedical Engineering › Nanoplatforms for cancer theranostics
Keywords
triple-negative breast cancer, ferroptosis, simvastatin, statins, HMGCR, mevalonate pathway, GPX4, Fe3O4 magnetic nanoparticles, nanomedicine, lipid peroxidation, drug resistance, MDA-MB-231 cells, tumor accumulation
MeSH terms
Ferroptosis, Animals, Delayed-Action Preparations, Drug Carriers, Female, Humans, Male, Mice, Nude, Signal Transduction, Simvastatin, Cell Line, Tumor, Mice, Magnetite Nanoparticles, MCF-7 Cells, Triple Negative Breast Neoplasms

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