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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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Citations

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Show all 8 references

Research works printed but not linked: 33

  1. Zhang T, Liu H, Li L, Guo ZY, Song J, Yang XY, Wan GY, Li RS, Wang YS. Leukocyte/platelet hybrid membrane-camouflaged dendritic large pore mesoporous silica nanoparticles co-loaded with photo/chemotherapeutic agents for triple negative breast cancer combination treatment. Bioact Mater. 2021;6:3865–78. · DOI
  2. Gong Y, Ji P, Yang YS, Xie S, Yu TJ, Xiao Y, Jin ML, Ma D, Guo LW, Pei YC, Chai WJ, Li DQ, Bai F, Bertucci F, Hu X, Jiang YZ, Shao ZM. Metabolic-pathway-based subtyping of triple-negative breast cancer reveals potential therapeutic targets. Cell Metab. 2021;33:51–64. · DOI
  3. Cao JY, Dixon SJ. Mechanisms of ferroptosis. Cell Mol Life Sci. 2016;73:2195–209. · DOI · Paper page
  4. Dixon SJ, Lemberg KM, Lamprecht MR, Skouta R, Zaitsev EM, Gleason CE, Patel DN, Bauer AJ, Cantley AM, Yang WS, Morrison B. Ferroptosis: An iron-dependent form of nonapoptotic cell death. Cell. 2012;149:1060–72. · DOI · Paper page
  5. Wang SF, Li FY, Qiao RR, Hu X, Liao HR, Chen LM, Wu JH, Wu HB, Zhao M, Liu JN, Chen R, Ma XB, Kim D, Sun JH, Davis TP, Chen CY, Tian J, Hyeon T, Ling D. Arginine-rich manganese silicate nanobubbles as a ferroptosis-inducing agent for tumor-targeted theranostics. ACS Nano. 2018;12:12380–92. · DOI
  6. Liu T, Liu W, Zhang M, Yu W, Gao F, Li C, Wang SB, Feng J, Zhang XZ. Ferrous-supply-regeneration nanoengineering for cancer-cell-specific ferroptosis in combination with imaging-guided photodynamic therapy. ACS Nano. 2018;12:12181–92. · DOI
  7. Stockwell BR, Angeli JPF, Bayir H, Bush AI, Conrad M, Dixon SJ, Fulda S, Gascon S, Hatzios SK, Kagan VE, Noel K, Jiang X, Linkermann A, Murphy ME, Overholtzer M, Oyagi A, Pagnussat GC, Park J, Ran Q, Rosenfeld CS, Salnikow K, Tang D, Torti FM, Torti SV, Toyokuni S, Woerpel KA, Zhang DD. Ferroptosis: a regulated cell death nexus linking metabolism, redox biology, and disease. Cell. 2017;171:273–85. · DOI · Paper page
  8. An Y, Zhu JD, Liu F, Deng J, Meng X, Liu GQ, Wu HY, Fan AP, Wang Z, Zhao YJ. Boosting the ferroptotic antitumor efficacy via site-specific amplification of tailored lipid peroxidation. ACS Appl Mater Interfaces. 2019;11:29655–66. · DOI
  9. Viswanathan VS, Ryan MJ, Dhruv HD, Gill S, Eichhoff OM, Seashore-Ludlow B, Kaffenberger SD, Eaton JK, Shimada K, Aguirre AJ, Viswanathan SR, Chattopadhyay S, Tamayo P, Yang WS, Rees MG, Chen S, Boskovic ZV, Javaid S, Huang C, Wu X, Tseng YY, Roider EM, Gao D, Cleary JM, Wolpin BM, Mesirov JP, Haber DA, Engelman JA, Boehm JS, Kotz JD, Hon CS, Chen Y, Hahn WC, Levesque MP, Doench JG, Berens ME, Shamji AF, Clemons PA, Stockwell BR, Schreiber SL. Dependency of a therapy-resistant state of cancer cells on a lipid peroxidase pathway. Nature. 2017;547:453–7. · DOI · Paper page
  10. Li HY, Shi W, Li XH, Hu YM, Fang Y, Ma HM. Ferroptosis accompanied by •OH generation and cytoplasmic viscosity increase revealed via dual-functional fluorescence probe. J Am Chem Soc. 2019;141:18301–7. · DOI
  11. Yu MY, Gai CC, Li ZHR, Ding DJ, Zheng J, Zhang WF, Lv SJ, Li WT. Targeted exosome-encapsulated erastin induced ferroptosis in triple negative breast cancer cells. Cancer Sci. 2019;110:3173–82. · DOI
  12. Hoque A, Chen H, Xu XC. Statin induces apoptosis and cell growth arrest in prostate cancer cells. Cancer Epidemiol Biomark Prev. 2008;17:88–94. · DOI
  13. Yin Y, Liu L, Zhao Z, Yin L, Bauer N, Nwaeburu CC, Gladkich J, Gross W, Hackert T, Sticht C, Gretz N, Strobel O, Herr I. Simvastatin inhibits sonic hedgehog signaling and stemness features of pancreatic cancer. Cancer Lett. 2018;426:14–24. · DOI
  14. Yu HT, Guo PY, Xie XZ, Wang Y, Chen G. Ferroptosis, a new form of cell death, and its relationships with tumourous diseases. J Cell Mol Med. 2017;21:648–57. · DOI
  15. Yang WS, Stockwell BR. Ferroptosis: death by lipid peroxidation. Trends Cell Biol. 2016;26:165–76. · DOI · Paper page
  16. Liu M, Liu B, Liu QQ, Du KK, Wang ZF, He NY. Nanomaterial-induced ferroptosis for cancer specific therapy. Coord Chem Rev. 2019;382:160–80. · DOI
  17. Wilhelm S, Tavares AJ, Dai Q, Ohta S, Audet J, Dvorak HF, Chan WCW. Analysis of nanoparticle delivery to tumours. Nat Rev Mater. 2016;1:1–12.
  18. Jiang Q, Liu Y, Guo RR, Yao XX, Sung S, Pang ZQ, Yang WL. Erythrocyte-cancer hybrid membrane-camouflaged melanin nanoparticles for enhancing photothermal therapy efficacy in tumors. Biomaterials. 2019;192:292–308. · DOI
  19. Liu J, Sun ZK, Deng YH, Zou Y, Li CY, Guo XH, Xiong LQ, Gao Y, Li FY, Zhao DY. Highly water-dispersible biocompatible magnetite particles with low cytotoxicity stabilized by citrate groups. Angew Chem Int Ed. 2009;48:5875–9. · DOI
  20. Zhang L, Xue H, Cao ZQ, Keefe A, Wang JN, Jiang SY. Multifunctional and degradable zwitterionic nanogels for targeted delivery, enhanced MR imaging, reduction-sensitive drug release, and renal clearance. Biomaterials. 2011;32:4604–8. · DOI
  21. Peng SJ, Ouyang BS, Men YZ, Du Y, Cao YB, Xie RH, Pang ZQ, Shen S, Yang WL. Biodegradable zwitterionic polymer membrane coating endowing nanoparticles with ultra-long circulation and enhanced tumor photothermal therapy. Biomaterials. 2020;231:119680. · DOI
  22. Wang F, Zhang YT, Yang P, Jin S, Yu M, Guo J, Wang CC. Fabrication of polymeric microgels using reflux-precipitation polymerization and its application for phosphoprotein enrichment. J Mater Chem B. 2014;2:2575–82. · DOI
  23. Zhai SY, Ma YH, Chen YY, Li D, Cao J, Liu YJ, Cai MT, Xie XX, Chen YW, Luo XL. Synthesis of an amphiphilic block copolymer containing zwitterionic sulfobetaine as a novel pH-sensitive drug carrier. Polym Chem. 2014;5:1285–97. · DOI
  24. Barry P, Vatsiou A, Spiteri I, Nichol D, Cresswell GD, Acar A, Trahearn N, Hrebien S, Garcia-Murillas I, Chkhaidze K, Ermini L, Huntingford IS, Cottom H, Zabaglo L, Koelble K, Khalique S, Rusby JE, Muscara F, Dowsett M, Maley CC, Natrajan R, Yuan Y, Schiavon G, Turner N, Sottoriva A. The spatiotemporal evolution of lymph node spread in early breast cancer. Clin Cancer Res. 2018;24:4763–70. · DOI
  25. Wang Y, Tang M. Corrigendum to PM2.5 induces ferroptosis in human endothelial cells through iron overload and redox imbalance. Environ Pollut (Barking, Essex: 1987). 2021;276:113640. · DOI
  26. Guo SD, Yao XX, Jiang Q, Wang K, Zhang YY, Peng HB, Yang WL. Dihydroartemisinin-loaded magnetic nanoparticles for enhanced chemodynamic therapy. Front Pharmacol. 2020;11:226. · DOI
  27. Lucky SS, Idris NM, Li ZQ, Huang K, Soo KC, Zhang Y. Titania coated upconversion nanoparticles for near-infrared light triggered photodynamic therapy. ACS Nano. 2015;9:191–205. · DOI
  28. Mandal CC, Ghosh-Choudhury N, Yoneda T, Choudhury GG. Simvastatin prevents skeletal metastasis of breast cancer by an antagonistic interplay between p53 and CD44. J Biol Chem. 2011;286:11314–27. · DOI · Paper page
  29. Hayano M, Yang WS, Corn CK, Pagano NC, Stockwell BR. Loss of cysteinyl-tRNA synthetase (CARS) induces the transsulfuration pathway and inhibits ferroptosis induced by cystine deprivation. Cell Death Differ. 2016;2:270–8. · DOI
  30. Chen G, Roy I, Yang C, Prasad PN. Nanochemistry and nanomedicine for nanoparticle-based diagnostics and therapy. Chem Rev. 2016;116:2826–85. · DOI
  31. Deng H, Li XL, Peng Q, Wang X, Chen JP, Li YD. Monodisperse magnetic single-crystal ferrite microspheres. Angew Chem Int Ed. 2005;44:2782–5. · DOI
  32. Yao XX, Yang P, Jin ZK, Jiang Q, Guo RR, Xie RH, He QJ, Yang WL. Multifunctional nanoplatform for photoacoustic imaging-guided combined therapy enhanced by CO induced ferroptosis. Biomaterials. 2019;197:268–83. · DOI
  33. Ryu JH, Jiwpanich S, Chacko R, Bickerton S, Thayumanavan S. Surface-functionalizable polymer nanogels with facile hydrophobic guest encapsulation capabilities. J Am Chem Soc. 2010;132:8246. · DOI

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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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