Doxorubicin-loaded NK exosomes enable cytotoxicity against triple-negative breast cancer spheroids | ||
| Iranian Journal of Basic Medical Sciences | ||
| مقاله 13، دوره 27، شماره 12، اسفند 2024، صفحه 1604-1615 اصل مقاله (977.66 K) | ||
| نوع مقاله: Original Article | ||
| شناسه دیجیتال (DOI): 10.22038/ijbms.2024.79378.17194 | ||
| نویسندگان | ||
| Zahra Sadat Hashemi* 1؛ Mahlegha Ghavami2؛ Fateme Mohammadi3؛ Mahdieh Shokrollahi Barough1؛ Farhad Shokati4؛ Saber Asghari1؛ saeed khalili5؛ Mandana Akbari Yekta4؛ Ardeshir Ghavamzadeh6؛ Ramin Sarrami Forooshani1 | ||
| 1ATMP Department, Breast Cancer Research Center, Motamed Cancer Institute, ACECR, Tehran, Iran | ||
| 2Pathology Department, Dalhousie University, Halifax, Canada | ||
| 3Department of Hematology, School of Allied Medical Sciences, Tehran University of Medical Sciences, Tehran, Iran | ||
| 4Biomaterials and Tissue Engineering Department, Breast Cancer Research Center, Motamed Cancer Institute, ACECR, Tehran, Iran | ||
| 5Department of Biology Sciences, Shahid Rajaee Teacher Training University, Tehran, Iran | ||
| 6Cancer and Cell Therapy Research Center, Tehran University of Medical Sciences, Tehran, Iran | ||
| چکیده | ||
| Objective(s): Natural killer (NK) cells are the most professional innate immune cells that initiate extracellular apoptosis via cytotoxic granules in malignant cells. Antitumoral properties of NK-derived exosomes (Exos) are attributed to their parent cells. Loading drugs into Exos as a carrier can enhance their effect and enable targeted delivery. In the present study, we aim to deliver Doxorubicin (DOX) to the breast cancer spheroids by NK-Exos. Materials and Methods: Peripheral blood mononuclear cells (PBMC) were used to harvest NK cells, and NK-Exos were isolated from NK cell expansion medium using an Exo-spinTM kit. DOX was loaded via the ultrasonication method. AO/EtBr, Annexin/PI, DAPI, MTT, and spheroids of human breast cancer were used to track the cytotoxic effect of DOX-NK-Exos. The colony formation assay, scratch and transwell assays, Real-Time PCR for p53 and VEGF-A, and WB for protein expression were also performed. Results: When compared to free DOX, all viability tests validated the inhibitory effects of DOX-NK-Exos. The obtained results indicated that DOX-NK-Exos selectively reduced tumor cell viability and spared fibroblast and MCF-10A as noncancerous cells. Long after spheroid treatment, DOX-NK-Exos’ remarkable effect persisted. Conclusion: Human breast carcinoma mass treated with DOX-NK-Exos underwent apoptosis and showed a strong inhibitory effect on proliferation. Thus, they can reduce the side effects of chemotherapeutics and can be used as drug carriers with selective toxicity. Additionally, the additive action of this combination formula results in a more severe loss in cell viability. | ||
| کلیدواژهها | ||
| Breast cancer؛ Cellular spheroid؛ Chemotherapy؛ Exosome؛ Natural killer cells | ||
| مراجع | ||
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1. Yang F, Teves SS, Kemp CJ, Henikoff S. Doxorubicin, DNA torsion, and chromatin dynamics. Biochim Biophys Acta 2014; 1845:84-89. 2. Tian Y, Li S, Song J, Ji T, Zhu M, Anderson GJ, et al. A doxorubicin delivery platform using engineered natural membrane vesicle exosomes for targeted tumor therapy. Biomaterials 2014; 35:2383-2390. 3. Foulkes WD, Smith IE, Reis-Filho JS. Triple-negative breast cancer. New England J Med 2010; 363:1938-1948. 4.Tung NM, Winer EP. Tumor-infiltrating lymphocytes and response to platinum in triple-negative breast cancer. J Clin Oncol 2015; 33: 969-971. 5. Cancello G, Bagnardi V, Sangalli C, Montagna E, Dellapasqua S, Sporchia A, et al. Phase II study with epirubicin, cisplatin, and infusional fluorouracil followed by weekly paclitaxel with metronomic cyclophosphamide as a preoperative treatment of triple-negative breast cancer. Clin Breast Cancer 2015; 15:259-265. 6. Torrisi R, Balduzzi A, Ghisini R, Rocca A, Bottiglieri L, Giovanardi F, et al. Tailored preoperative treatment of locally advanced triple negative (hormone receptor negative and HER2 negative) breast cancer with epirubicin, cisplatin, and infusional fluorouracil followed by weekly paclitaxel. Cancer Chemother Pharmacol 2008; 62:667-672. 7. Pérez-Herrero E, Fernández-Medarde A. Advanced targeted therapies in cancer: Drug nanocarriers, the future of chemotherapy. Eur J Pharm Biopharm 2015; 93:52-79. 8. Hashemi ZS, Ghavami M, Kashyap MK. Exosomes, miRNAs, and lncRNAs in breast cancer: Therapeutic and diagnostic applications. Front Genet 2023; 14:1192866. 9. Johnsen KB, Gudbergsson JM, Skov MN, Pilgaard L, Moos T, Duroux M. A comprehensive overview of exosomes as drug delivery vehicles - endogenous nanocarriers for targeted cancer therapy. Biochim Biophys Acta 2014; 1846:75-87. 10. Fath MK, Naderi M, Hamzavi H, Ganji M, Shabani S, Khalesi B, et al. Molecular mechanisms and therapeutic effects of different vitamins and minerals in COVID-19 patients. J Trace Elem Med Biol 2022; 73:127044. 11. Kooijmans S, Fliervoet L, Van Der Meel R, Fens M, Heijnen H, en Henegouwen PvB, et al. PEGylated and targeted extracellular vesicles display enhanced cell specificity and circulation time. J Control Release 2016; 224:77-85. 12. Schindler C, Collinson A, Matthews C, Pointon A, Jenkinson L, Minter RR, et al. Exosomal delivery of doxorubicin enables rapid cell entry and enhanced in vitro potency. PLoS One 2019; 14:e0214545. 13. Alvarez-Erviti L, Seow Y, Yin H, Betts C, Lakhal S, Wood MJ. Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes. Nat Biotechnol 2011; 29:341-345. 14. Gong C, Tian J, Wang Z, Gao Y, Wu X, Ding X, et al. Functional exosome-mediated co-delivery of doxorubicin and hydrophobically modified microRNA 159 for triple-negative breast cancer therapy. J Nanobiotechnology 2019; 17:1-18. 15. Hatami Z, Hashemi ZS, Eftekhary M, Amiri A, Karpisheh V, Nasrollahi K, et al. Natural killer cell-derived exosomes for cancer immunotherapy: innovative therapeutics art. Cancer Cell Int 2023; 23:1-18. 16. Kumar DN, Chaudhuri A, Aqil F, Dehari D, Munagala R, Singh S, et al. Exosomes as emerging drug delivery and diagnostic modality for breast cancer: Recent advances in isolation and application. Cancers 2022; 14:1435. 17. Gomari H, Moghadam MF, Soleimani M, Ghavami M, Khodashenas S. Targeted delivery of doxorubicin to HER2 positive tumor models. Int J Nanomedicine 2019; 14:5679-5690. 18. Parvin D, Hashemi ZS, Shokati F, Mohammadpour Z, Bazargan V. Immunomagnetic Isolation of HER2-Positive Breast Cancer Cells Using a Microfluidic Device. ACS Omega 2023; 8: 21745–21754. 19. Ryan S-L, Baird A-M, Vaz G, Urquhart AJ, Senge h, Richard DJ, et al. Drug discovery approaches utilizing three-dimensional cell culture. Assay Drug Dev Technol 2016; 14:19-28. 20. Hashemi ZS, Moghadam MF, Soleimani M. Comparison of the ex vivo expansion of UCB-derived CD34+ in 3D DBM/MBA scaffolds with USSC as a feeder layer. Iran J Basic Med Sci 2013; 16:1075-1087. 21. Hashemi ZS, Moghadam MF, Soleimani M, Hafizi M, Amirizadeh N. TGF-b downregulation by RNAi technique in ex vivo-expanded HSCs on 3D DBM scaffold. Tehran Univ Med J 2012; 70: 86-95. 22. Goodman TT, Ng CP, Pun SH. 3-D tissue culture systems for the evaluation and optimization of nanoparticle-based drug carriers. Bioconjug Chem 2008; 19: 1951-1959. 23. Ramamoorthy P, Thomas SM, Kaushik G, Subramaniam D, Chastain KM, Dhar A, et al. Metastatic tumor-in-a-dish, a novel multicellular organoid to study lung colonization and predict therapeutic response. Cancer Res 2019; 79: 1681-1695. 24. Bordanaba-Florit G, Madarieta I, Olalde B, Falcón-Pérez JM, Royo F. 3D cell cultures as prospective models to study extracellular vesicles in cancer. Cancers 2021; 13: 307-322. 25. Shimasaki N, Coustan-Smith E, Kamiya T, Campana D. Expanded and armed natural killer cells for cancer treatment. Cytotherapy 2016; 18: 1422-1434. 26. Mohammadi F, Hashemi ZS, Forooshani RS, Alizadeh S. Bioactivity of exosomes derived from trained natural killer cells versus non-trained one: More functional and antitumor activity. Biomed Res Int 2022; 2022:1-11. 27. Chen X, Han J, Chu J, Zhang L, Zhang J, Chen C, et al. A combinational therapy of EGFR-CAR NK cells and oncolytic herpes simplex virus 1 for breast cancer brain metastases. Oncotarget 2016; 7:27764. 28. Ruggeri L, Capanni M, Urbani E, Perruccio K, Shlomchik WD, Tosti A, et al. Effectiveness of donor natural killer cell alloreactivity in mismatched hematopoietic transplants. Science 2002; 295: 2097-2100. 29. Lugini L, Cecchetti S, Huber V, Luciani F, Macchia G, Spadaro F, et al. Immune surveillance properties of human NK cell-derived exosomes. J Immunol 2012; 189: 2833-2842. 30. Zhu L, Kalimuthu S, Gangadaran P, Oh JM, Lee HW, Baek SH, et al. Exosomes derived from natural killer cells exert therapeutic effect in melanoma. Theranostics 2017; 7: 2732. 31. Zhu L, Oh JM, Gangadaran P, Kalimuthu S, Baek SH, Jeong SY, et al. Targeting and therapy of glioblastoma in a mouse model using exosomes derived from natural killer cells. Front Immunol 2018; 9: 824. 32. Ahmadvand M, Barough MS, Hashemi ZS, Sanati H, Abbasvandi F, Yunesian M, et al. Safety and feasibility study of ex vivo expanded allogeneic-NK cells infusion in patients with acute pneumonia caused by COVID-19. Pilot Feasibility Stud 2023; 9: 1-13. 33. Hashemi ZS, Ghavami M, Kiaie SH, Mohammadi F, Barough MS, Khalili S, et al. Novel delivery of sorafenib by natural killer cell-derived exosomes-enhanced apoptosis in triple-negative breast cancer. Nanomedicine 2023; 18: 437-453. 34. Hashemi ZS, Moghadam MF, Khalili S, Ghavami M, Salimi F, Sadroddiny E. Additive effect of metastamiR-193b and breast cancer metastasis suppressor 1 as an anti-metastatic strategy. Breast Cancer 2018: 1-14. 35. Hashemi ZS, Forouzandeh Moghadam M, Soleimani M. Comparison of TGFbR2 down-regulation in expanded HSCs on MBA/DBM scaffolds coated by UCB stromal cells. In vitro Cell Dev Biol Anim 2015; 51: 495-506. 36. Hashemi ZS, Moghadam MF, Sadroddiny E. Varying miR-193b-3p expression patterns in breast cancer cell lines indicates its potential for cancer management strategies. Int J Cancer Manag 2018; 11: e63540. 37. Hashemi ZS, Moghadam MF, Farokhimanesh S, Rajabibazl M, Sadroddiny E. Inhibition of breast cancer metastasis by co-transfection of miR-31/193b-mimics. Iran J Basic Med Sci 2018; 21: 427-433. 38. Imamura Y, Mukohara T, Shimono Y, Funakoshi Y, Chayahara N, Toyoda M, et al. Comparison of 2D-and 3D-culture models as drug-testing platforms in breast cancer. Oncol Rep 2015; 33: 1837-1843. 39. Brenton JD, Carey LA, Ahmed AA, Caldas C. Molecular classification and molecular forecasting of breast cancer: ready for clinical application? J Clin Oncol 2005; 23: 7350-7360. 40. Sørlie T, Perou CM, Tibshirani R, Aas T, Geisler S, Johnsen H, et al. Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci U S A 2001; 98: 10869-10874. 41. Han D, Wang K, Zhang T, Gao G, Xu H. Natural killer cell-derived exosome-entrapped paclitaxel can enhance its anti-tumor effect. Eur Rev Med Pharmacol Sci 2020; 24: 5703-5713. 42. Wu F, Xie M, Hun M, She Z, Li C, Luo S, et al. Natural Killer Cell-Derived Extracellular Vesicles: Novel Players in Cancer Immunotherapy. Front Immunol 2021; 12: 1970. 43. Neviani P, Wise PM, Murtadha M, Liu CW, Wu C-H, Jong AY, et al. Natural killer–derived exosomal miR-186 inhibits neuroblastoma growth and immune escape mechanisms. Cancer Res 2019; 79: 1151-1164. 44. Choi J-W, Lim S, Kang JH, Hwang SH, Hwang K-C, Kim SW, et al. Proteome analysis of human natural killer cell derived extracellular vesicles for identification of anticancer effectors. Molecules 2020; 25: 5216. 45. Federici C, Shahaj E, Cecchetti S, Camerini S, Casella M, Iessi E, et al. Natural-killer-derived extracellular vesicles: Immune sensors and interactors. Front Immunol 2020; 11: 262. 46. Kim MS, Haney MJ, Zhao Y, Mahajan V, Deygen I, Klyachko NL, et al. Development of exosome-encapsulated paclitaxel to overcome MDR in cancer cells. Nanomedicine 2016; 12: 655-664. 47. Mutlu EC, Kaya Ö, Wood M, Mager I, Topkara KÇ, Çamsarı Ç, et al. Efficient doxorubicin loading to isolated dexosomes of immature JAWSII cells: Formulated and characterized as the bionanomaterial. Materials 2020; 13: 3344. 48. Chen P, Wang Z, Zong S, Zhu D, Chen H, Zhang Y, et al. pH-sensitive nanocarrier based on gold/silver core–shell nanoparticles decorated multi-walled carbon manotubes for tracing drug release in living cells. Biosens Bioelectron 2016; 75: 446-451. 49. Iessi E, Logozzi M, Lugini L, Azzarito T, Federici C, Spugnini EP, et al. Acridine Orange/exosomes increase the delivery and the effectiveness of Acridine Orange in human melanoma cells: A new prototype for theranostics of tumors. J Enzyme Inhib Med Chem 2017; 32: 648-657. 50. Wei H, Chen J, Wang S, Fu F, Zhu X, Wu C, et al. A nanodrug consisting of doxorubicin and exosome derived from mesenchymal stem cells for osteosarcoma treatment in vitro. Int J Nanomedicine 2019; 14: 8603. 51. Cui X, Hartanto Y, Zhang H. Advances in multicellular spheroids formation. J R Soc Interface 2017; 14: 20160877. 52. Chen L, Brigstock DR. Integrins and heparan sulfate proteoglycans on hepatic stellate cells (HSC) are novel receptors for HSC‐derived exosomes. FEBS Lett 2016; 590: 4263-4274. 53. Zhu R, Wang Z, Liang P, He X, Zhuang X, Huang R, et al. Efficient VEGF targeting delivery of DOX using Bevacizumab conjugated SiO2@ LDH for anti-neuroblastoma therapy. Acta Biomater 2017; 63: 163-180. 54. Guerriero E, Sorice A, Capone F, Storti G, Colonna G, Ciliberto G, et al. Combining doxorubicin with a phenolic extract from flaxseed oil: Evaluation of the effect on two breast cancer cell lines. Int J Oncol 2017; 50: 468-476. 55. Hamadneh L, Abu-Irmaileh B, Al-Majawleh M, Bustanji Y, Jarrar Y, Al-Qirim T. Doxorubicin–paclitaxel sequential treatment: insights of DNA methylation and gene expression changes of luminal A and triple negative breast cancer cell lines. Mol Cell Biochem 2021; 476: 1-8. 56. Chavez KJ, Garimella SV, Lipkowitz S. Triple negative breast cancer cell lines: one tool in the search for better treatment of triple negative breast cancer. Breast Dis 2010; 32: 35. 57. Srivastava A, Amreddy N, Babu A, Panneerselvam J, Mehta M, Muralidharan R, et al. Nanosomes carrying doxorubicin exhibit potent anticancer activity against human lung cancer cells. Sci Rep 2016; 6: 1-15. 58. Toffoli G, Hadla M, Corona G, Caligiuri I, Palazzolo S, Semeraro S, et al. Exosomal doxorubicin reduces the cardiac toxicity of doxorubicin. Nanomedicine 2015; 10: 2963-2971. | ||
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