Natural Killer Cell-Derived Exosome Mimetics as Natural Nanocarriers for In Vitro Delivery of Chemotherapeutics to Thyroid Cancer Cells
DOI:
https://doi.org/10.15407/exp-oncology.2024.04.358Keywords:
thyroid cancer, exosome mimetics, natural killer cells, immunotherapy, drug delivery systemAbstract
Background. Exosomes have become a potential field of nanotechnology for the treatment and identification of many disorders. However, the generation of exosomes is a difficult, time-consuming, and low-yielding procedure. At the same time, exosome mimetics (EM) resemble exosomes in their characteristics but have higher production yields. The aim of this study was to produce natural killer (NK) cell-derived EM (NKEM) loaded with sorafenib and test their killing ability against thyroid cancer cell lines. Materials and Methods. Sorafenib was loaded into NKEM by mixing sorafenib with NK cells during NKEM production (NKEM-S). Then, these two types of nanoparticles were characterized with nanoparticle tracking analysis (NTA) to measure their sizes. In addition, the cellular uptake and in vitro killing effect of NKEM-S on thyroid cancer cell lines were investigated using confocal laser microscopy and bioluminescence imaging (BLI) techniques. Results. The uptake of NKEM and NKEM-S by the thyroid cancer cells was observed. Moreover, BLI confirmed the killing and anti-proliferation effect of NKEM-S on two thyroid cancer cell lines. Especially important, the NKEM-S demonstrated a desirable killing effect even for anaplastic thyroid cancer (ATC) cells. Conclusion. Sorafenib-loaded NKEM showed the ability to kill thyroid cancer cells in vitro, even against ATC. This provides a new opportunity for drug delivery systems and thyroid cancer treatment.
References
Araque KA, Gubbi S, Klubo-Gwiezdzinska J. Updates on the management of thyroid cancer. Horm Metab Res. 2020;52(8):562-577. https://doi.org/10.1055/a-1089-7870
Oh JM, Ahn BC. Molecular mechanisms of radioactive iodine refractoriness in differentiated thyroid cancer: Im- paired sodium iodide symporter (NIS) expression owing to altered signaling pathway activity and intracellular localization of NIS. Theranostics. 2021; 11(13):6251-6277. https://doi.org/10.7150/thno.57689
Fagin JA, Wells Jr. SA. Biologic and clinical perspectives on thyroid cancer. N Engl J Med. 2016;375(11):1054-1067. https://doi.org/10.1056/NEJMra1501993
Bible KC, Kebebew E., Brierley J, et al. 2021 American Thyroid Association guidelines for management of patients with anaplastic thyroid cancer. Th roid. 2021;31(3):337-386. https://doi.org/10.1089/thy.2020.0944
Tuccilli C, Baldini E, Sorrenti S, et al. CTLA-4 and PD-1 ligand gene expression in epithelial thyroid cancers. Int J En- docrinol. 2018;2018:1742951. https://doi.org/10.1155/2018/1742951
Subbiah V, Kreitman RJ, Wainberg ZA, et al. Dabrafenib and Trametinib treatment in patients with locally advanced or metastatic BRAF V600-mutant anaplastic thyroid cancer. J Clin Oncol. 2018;36(1):7-13. https://doi.org/10.1200/ JCO.2017.73.6785.
Lee CH, Jung JH, Son SH, et al. Risk factors for radioactive iodine-avid metastatic lymph nodes on post I-131 abla- tion SPECT/CT in low- or intermediate-risk groups of papillary thyroid cancer. PLoS One. 2018;13(8):e0202644. https://doi.org/10.1371/journal.pone.0202644
Jeong JH, Kong EJ, Jeong SY, et al. Clinical outcomes of low-dose and high-dose postoperative radioiodine therapy in patients with intermediate-risk differentiated thyroid cancer. Nucl Med Commun. 2017;38(3):228-233. https://doi. org/10.1097/MNM.0000000000000636
Liang JJ, Feng WJ, Li R, et al. Analysis of the value and safety of thyroid-stimulating hormone in the clinical efficacy of patients with thyroid cancer. World J Clin Cases. 2023;11(5):1058-1067. https://doi.org/10.12998/wjcc.v11.i5.1058
Zhu L, Li XJ, Kalimuthu S, et al. Natural killer cell (NK-92MI)-based therapy for pulmonary metastasis of anaplastic thyroid cancer in a nude mouse model. Front Immunol. 2017;8:816. https://doi.org/10.3389/fimmu.2017.00816
Gounder MM, Mahoney MR, Van Tine BA, et al. Sorafenib for advanced and refractory desmoid tumors. N Engl J Med. 2018;379(25):2417-2428. https://doi.org/10.1056/NEJMoa1805052
Sumbly V, Landry I, Sneed C, et al. Leukemic stem cells and advances in hematopoietic stem cell transplantation for acute myeloid leukemia: a narrative review of clinical trials. Stem Cell Investig. 2022;9:10. https://doi.org/10.21037/ sci-2022-044
Feng F, Jiang Q, Jia H, et al. Which is the best combination of TACE and Sorafenib for advanced hepatocellular car- cinoma treatment? A systematic review and network meta-analysis. Pharmacol Res. 2018. https://doi.org/10.1016/j. phrs.2018.06.021
Thomas L, Lai SY, Dong W, etal. Sorafenibinmetastaticthyroidcancer: asystematicreview. Oncologist. 2014;19(3):251-
https://doi.org/10.1634/theoncologist.2013-0362
Rehman FU, Liu Y, Zheng M, Shi B. Exosomes based strategies for brain drug delivery. Biomaterials. 2022;293:121949. https://doi.org/10.1016/j.biomaterials.2022.121949
Mondal J, Pillarisetti S, Junnuthula V, et al. Hybrid exosomes, exosome-like nanovesicles and engineered exosomes for therapeutic applications. J Control Release. 2022; 353:1127-1149. https://doi.org/10.1016/j.jconrel.2022.12.027
Aarsund M, Nyman TA, Stensland ME, et al. Isolation of a cytolytic subpopulation of extracellular vesicles derived from NK cells containing NKG7 and cytolytic proteins. Front Immunol. 2022;13:977353. https://doi.org/10.3389/ fimmu.2022.977353
Aarsund M, Segers FM, Wu Y, et al. Comparison of characteristics and tumor targeting properties of extracellular vesicles derived from primary NK cells or NK-cell lines stimulated with IL-15 or IL-12/15/18. Cancer Immunol Im- munother. 2022;71(9):2227-2238. https://doi.org/10.1007/s00262-022-03161-0
Enomoto Y, Li P, Jenkins LM, et al. Cytokine-enhanced cytolytic activity of exosomes from NK Cells. Cancer Gene Ther. 2022;29(6):734-749. https://doi.org/10.1038/s41417-021-00352-2
Fabbri M. Natural Killer Cell-derived vesicular miRNAs: a new anticancer approach? Cancer Res. 2020;80(1):17-22. https://doi.org/10.1158/0008-5472.CAN-19-1450
Han D, Wang K, Zhang T, et al. Natural killer cell-derived exosome-entrapped paclitaxel can enhance its anti-tumor effect. Eur Rev Med Pharmacol Sci. 2020;24(10):5703-5713. https://doi.org/10.26355/eurrev_202005_21362
Wang G, Hu W, Chen H, et al. Cocktail strategy based on NK cell-derived exosomes and their biomimetic nanopar- ticles for dual tumor therapy. Cancers (Basel). 2019;11(10):1560. https://doi.org/10.3390/cancers11101560
Wu J, Wu D, Wu G, et al. Scale-out production of extracellular vesicles derived from natural killer cells via me- chanical stimulation in a seesaw-motion bioreactor for cancer therapy. Biofabrication. 2022; 14(4). https://doi. org/10.1088/1758-5090/ac7eeb
Zhao M, van Straten D, Broekman MLD, et al. Nanocarrier-based drug combination therapy for glioblastoma. Thera- nostics. 2020;10(3):1355-1372. https://doi.org/10.7150/thno.38147
Rehman FU, Liu Y, Zheng Y, Shi B. Exosomes based strategies for brain drug delivery. Biomaterials. 2023;293:121949. https://doi.org/10.1016/j.biomaterials.2022.121949
Lakhal S, Wood MJ. Exosome nanotechnology: an emerging paradigm shift in drug delivery: exploitation of exo- some nanovesicles for systemic in vivo delivery of RNAi heralds new horizons for drug delivery across biological barriers. Bioessays. 2011;33(10):737-741. https://doi.org/10.1002/bies.201100076
Kim SM, Kim HS. Engineering of extracellular vesicles as drug delivery vehicles. Stem Cell Investig. 2017;4:74. https:// doi.org/10.21037/sci.2017.08.07
Kim OY, Lee J, Gho YS. Extracellular vesicle mimetics: Novel alternatives to extracellular vesicle-based theranostics, drug delivery, and vaccines. Semin Cell Dev Biol. 2017;67:74-82. https://doi.org/10.1016/j.semcdb.2016.12.001
Sun JX, Xu JZ, An Y, et al. Future in precise surgery: Fluorescence-guided surgery using EVs derived fluorescence contrast agent. J Control Release. 2022;353:832-841. https://doi.org/10.1016/j.jconrel.2022.12.013
Shao J, Zaro J, Shen Y. Advances in exosome-based drug delivery and tumor targeting: from tissue distribution to in- tracellular fate. Int J Nanomedicine. 2020;15:9355-9371. https://doi.org/10.2147/IJN.S281890
Zheng X, Sun K, Liu Y, et al. Resveratrol-loaded macrophage exosomes alleviate multiple sclerosis through targeting microglia. J Control Release. 2022;353:675-684. https://doi.org/10.1016/j.jconrel.2022.12.026
Li J, Li J, Peng Y, et al. Dendritic cell derived exosomes loaded neoantigens for personalized cancer immunotherapies.
J Control Release. 2022;353:423-433. https://doi.org/10.1016/j.jconrel.2022.11.053
Jia R, Cui K, Li Z, et al. NK cell-derived exosomes improved lung injury in mouse model of Pseudomonas aeruginosa lung infection. J Physiol Sci. 2020;70(1):50. https://doi.org/10.1186/s12576-020-00776-9
Li D, Wang Y, Jin X, et al. NK cell-derived exosomes carry miR-207 and alleviate depression-like symptoms in mice.
J Neuroinflammation. 2020;17(1):126. https://doi.org/10.1186/s12974-020-01787-4
Wang L, Wang Y, Quan J. Exosomal miR-223 derived from natural killer cells inhibits hepatic stellate cell activation by suppressing autophagy. Mol Med. 2020;26(1):81. https://doi.org/10.1186/s10020-020-00207-w
Federici C, Shahaj E, Cecchetti S, et al. Natural-Killer-derived extracellular vesicles: immune sensors and interactors.
Front Immunol. 2020;11:262. https://doi.org/10.3389/fimmu.2020.00262
Kim OY, Park HT, Dinh NTH, et al. Bacterial outer membrane vesicles suppress tumor by interferon-gamma-me- diated antitumor response. Nat Commun. 2017;8(1):626. https://doi.org/10.1038/s41467-017-00729-8.
Kim OY, Choi SJ, Jang SC, et al. Bacterial protoplast-derived nanovesicles as vaccine delivery system against bacterial infection. Nano Lett. 2015;15(1):266-274. https://doi.org/10.1021/nl503508h
Kim OY, Dinh NT, Park HT, et al. Bacterial protoplast-derived nanovesicles for tumor targeted delivery of chemo- therapeutics. Biomaterials. 2017;113:68-79. https://doi.org/10.1016/j.biomaterials.2016.10.037
Goh WJ, Zou S, Ong WY, et al. Bioinspired cell-derived nanovesicles versus exosomes as drug delivery systems: a cost-effective alternative. Sci Rep. 2017;7(1):14322. https://doi.org/10.1038/s41598-017-14725-x
Jang SC, Kim OY, Yoon CM, et al. Bioinspired exosome-mimetic nanovesicles for targeted delivery of chemothera- peutics to malignant tumors. ACS Nano. 2013;7(9):7698-7710. https://doi.org/10.1021/nn402232g
Liu H, Deng S, Han L, et al. Mesenchymal stem cells, exosomes and exosome-mimics as smart drug carriers for targeted cancer therapy. Colloids Surf B Biointerfaces. 2022;209(Pt 1):112163. https://doi.org/10.1016/j.col- surfb
Wang J, Li M, Jin L, et al. Exosome mimetics derived from bone marrow mesenchymal stem cells deliver doxoru- bicin to osteosarcoma in vitro and in vivo. Drug Deliv. 2022;29(1):3291-3303. https://doi.org/10.1080/10717544.2 022.2141921
Zhang W, Wang L, Guo H, et al. Dapagliflozin-loaded exosome mimetics facilitate diabetic wound healing by HIF- 1alpha-mediated enhancement of angiogenesis. Adv Healthc Mater. 2022:e2202751. https://doi.org/10.1002/ adhm.202202751
Rajendran RL, Gangadaran P, Kwack MH, et al. Engineered extracellular vesicle mimetics from macrophage pro- motes hair growth in mice and promotes human hair follicle growth. Exp Cell Res. 2021;409(1):112887. https://doi. org/10.1016/j.yexcr.2021.112887
Zhu L, Kalimuthu S, Gangadaran P, et al. Exosomes derived from Natural Killer Cells exert therapeutic effect in me- lanoma. Theranostics. 2017;7(10):2732-2745. https://doi.org/10.7150/thno.18752
Kalimuthu S, Gangadaran P, Rajendran RL, et al. A new approach for loading anticancer drugs into mesenchy- mal stem cell-derived exosome mimetics for cancer therapy. Front Pharmacol. 2018;9:1116. https://doi.org/10.3389/ fphar.2018.01116.
Gangadaran P, Hong СМ, Oh JM, et al. In vivo non-invasive imaging of radio-labeled exosome-mimetics derived from red blood cells in mice. Front Pharmacol. 2018;9:817. https://doi.org/10.3389/fphar.2018.00817.
Gangadaran P, Rajendran RL, Lee HW, et al. Extracellular vesicles from mesenchymal stem cells activates VEGF re- ceptors and accelerates recovery of hindlimb ischemia. J Control Release. 2017;264:112-126. https://doi.org/:10.1016/j. jconrel.2017.08.022.
Kalimuthu S, Gangadaran P, Li XJ, et al. in vivo therapeutic potential of mesenchymal stem cell-derived extracel- lular vesicles with optical imaging reporter in tumor mice model. Sci Rep. 2016;6:30418. https://doi.org/10.1038/ srep30418.
Imai T, Takahashi Y, Nishikawa M, et al. Macrophage-dependent clearance of systemically administered B16BL6- derived exosomes from the blood circulation in mice. J Extracell Vesicles. 2015;4:26238. https://doi.org/10.3402/jev. v4.26238
Vadevoo SMP, Kim JE, Gunassekaran GR, et al. IL4 receptor-targeted proapoptotic peptide blocks tumor growth and metastasis by enhancing antitumor immunity. Mol Cancer Ther. 2017;16(12):2803-2816. https://doi. org/10.1158/1535-7163.MCT-17-0339
Munagala R, Aqil F, Jeyabalan J, Gupta RC. Bovine milk-derived exosomes for drug delivery. Cancer Lett. 2016;371(1):48-61. https://doi.org/10.1016/j.canlet.2015.10.020
Vashisht M, Rani P, Onteru SK, Singh D. Curcumin encapsulated in milk exosomes resists human digestion and pos- sesses enhanced intestinal permeability in vitro. Appl Biochem Biotechnol. 2017;183(3):993-1007. https://doi. org/10.1007/s12010-017-2478-4.
Haney MJ, Klyachko NL, Zhao Y, et al. Exosomes as drug delivery vehicles for Parkinson's disease therapy. J Control Release. 2015;207:18-30. https://doi.org/10.1016/j.jconrel.2015.03.033
Xin H, Li Y, Buller B, et al. Exosome-mediated transfer of miR-133b from multipotent mesenchymal stromal cells to neural cells contributes to neurite outgrowth. Stem Cells. 2012;30(7):1556-1564. https://doi.org/:10.1002/stem.1129
Katakowski M, Buller B, Zheng X, et al. Exosomes from marrow stromal cells expressing miR-146b inhibit glioma growth. Cancer Lett. 2013;335(1):201-204. https://doi.org/10.1016/j.canlet.2013.02.019
Sun D, Zhuang X, Xiang X, et al. A novel nanoparticle drug delivery system: the anti-inflammatory activity of cur- cumin is enhanced when encapsulated in exosomes. Mol Ther. 2010;18(9):1606-1614. https://doi.org/10.1038/ mt.2010.105
Hu CM, Fang RH, Wang KC, et al. Nanoparticle biointerfacing by platelet membrane cloaking. Nature.
;526(7571):118-121. https://doi.org/10.1038/nature15373
Wei X, Ying M, Dehaini D, et al. Nanoparticle functionalization with platelet membrane enables multifactored biological targeting and detection of atherosclerosis. ACS Nano. 2017;12(1):109-116. https://doi.org/10.1021/ acsnano.7b07720
Molinaro R, Corbo C, Martinez JO, et al. Biomimetic proteolipid vesicles for targeting inflamed tissues. Nat Mater.
;15(9):1037-1046. https://doi.org/10.1038/nmat4644
Oh K, Kim SR, Kim DK, et al. In vivo differentiation of therapeutic insulin-producing cells from bone marrow cells via extracellular vesicle-mimetic nanovesicles. ACS Nano. 2015;9(12):11718-11727. https://doi.org/10.1021/ acsnano.5b02997
Hashemi ZS, Ghavami M, Kiaie SH, et al. Novel delivery of sorafenib by natural killer cell-derived exosomes-enhanced apoptosis in triple-negative breast cancer. Nanomedicine (Lond). 2023;18(5):437-453. https://doi.org/10.2217/nnm- 2022-0237
Tan S, Wu T, Zhang D, Zhang Z. Cell or cell membrane-based drug delivery systems. Theranostics. 2015;5(8):863- 881. https://doi.org/10.7150/thno.11852
Yuan D, Zhao Y, Banks WA, et al. Macrophage exosomes as natural nanocarriers for protein delivery to inflamed brain. Biomaterials. 2017;142:1-12. https://doi.org/10.1016/j.biomaterials.2017.07.011
Essola JM, Zhang M, Yang H, et al. Exosome regulation of immune response mechanism: Pros and cons in immuno- therapy. Bioact Mater. 2024;32:124-146. https://doi.org/10.1016/j.bioactmat.2023.09.018
Tan L, Han S, Ding S, et al. Chitosan nanoparticle-based delivery of fused NKG2D-IL-21 gene suppresses colon cancer growth in mice. Int J Nanomedicine. 2017;12:3095-3107. https://doi.org/10.2147/IJN.S128032
Wu D, Shou X, Zhang Y, et al. Cell membrane-encapsulated magnetic nanoparticles for enhancing natural killer cell- mediated cancer immunotherapy. Nanomedicine. 2021;32:102333. https://doi.org/10.1016/j.nano.2020.102333
Pitchaimani A, Nguyen TDT, Marasini R, et al. Biomimetic Natural Killer membrane camouflaged polymeric nanopar- ticle for targeted bioimaging. Adv Funct Mater. 2019;29(4):1806817. https://doi.org/10.1002/adfm.201806817
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