انتقال هدفمند داروی السکلومول به سلول های سرطانی روده بزرگ با سامانه حمل دارویی هدفمند سیلیکا میان تخلخل مغناطیسی

محورهای موضوعی : شیمی آلی

مجتبی تارین ¹ (دانشجوی دکترای گروه شیمی، دانشکده علوم، دانشگاه فردوسی مشهد، مشهد، ایران.)
مریم بابایی ² (دکترای شیمی آلی، گروه شیمی، دانشکده علوم، دانشگاه فردوسی مشهد، مشهد، ایران.)
حسین عشقی ³ (استاد شیمی آلی، گروه شیمی، دانشکده علوم، دانشگاه فردوسی مشهد، مشهد، ایران.)
مریم مقدم متین ⁴ (استاد زیست شناسی، گروه زیست شناسی، دانشکده علوم، دانشگاه فردوسی مشهد، مشهد، ایران.)
امیر شکوه سلجوقی ⁵ (دانشیار شیمی معدنی، گروه شیمی، دانشکده علوم، دانشگاه فردوسی مشهد، مشهد، ایران.)

تاریخ دریافت : 1402/02/25 تاریخ پذیرش : 1402/04/13 تاریخ انتشار : 1402/09/01

کلید واژه: دارورسانی هدفمند, سرطان روده بزرگ, السکلومول, نانوذره‌های میان(مزو)تخلخل سیلیکا, واپایش رهایش دارو,

چکیده مقاله :

در این پژوهش، انتقال هدفمند داروی پادسرطانی السکلومول به سلول های سرطانی روده بزرگ از راه گسترش نانوذره های میان(مزو)تخلخل سیلیکای مغناطیسی (MMSNs) و پیوند عامل های متفاوت مانند واپایش گرهای دریچه ای طلا، بسپار پلی اتیلن گلیکول (PEG) دوعاملی و آپتامر مربوط به مولکول های چسبنده سطح سلول های اپی تلیالی (EpCAM) به سطح نانوحامل صورت گرفت. پس از سنتز سامانه حمل دارویی، ویژگی های فیزیکی-شیمیایی آن ارزیابی شدند. همچنین، ویژگی پادسرطانی داروی السکلومول و سامانه حمل دارویی با لیگاند ویژه آپتامر EpCAM و بدون آن در شرایط برون تنی مقایسه شد. بررسی تصویرهای میکروسکوپ الکترونی نشان داد که نانوذره های MMSNs کروی با قطر حدود 19 نانومتر بودند. السکلومول با موفقیت در حفره های باز این نانوذره ها بارگذاری شد و درصد بارگذاری حدود 39 درصد تخمین زده شد. همچنین، پس از فرایند درپوش گذاری و مسدوسازی حفره ها، نانوذره های Au-ELC-MMSN-NH2 در طی 96 ساعت، رهایش پیوسته و وابسته به pH نشان دادند. نتیجه هایMTT نشان داد که این نانوذره ها سمیت چشمگیری را در برابر سلول های سرطانی روده بزرگ و بیان کننده گیرنده EpCAM در مقایسه با سلول های CHO اعمال می کنند. با توجه به نتیجه های امیدوارکننده APT-PEG-Au-ELC-MMSN-NH2، سامانه تهیه شده می تواند به عنوان جایگزین درمانی السلکومول برای سرطان روده بزرگ استفاده شود. هرچند، پیش از استفاده گسترده آن در حوزه بالینی، به آزمایش های بیشتری نیاز است.

چکیده انگلیسی:

In this research, the targeted delivery of elesclomol to colorectal cancer cells was explored through the development of magnetic mesoporous silica nanoparticles (MMSNs) loaded with elesclomol and surface modification with gold gatekeepers, bifunctional polyethylene glycol (PEG) polymer, and epithelial cell adhesion molecule (EpCAM) aptamers to improve drug delivery performance. The physicochemical properties of nanocarriers were characterized and the cellular toxicity of elesclomol, and nano-delivery system with and without EpCAM aptamer modification has been investigated in vitro. High resolution transmission electron microscopy (HRTEM) and field emission scanning electron microscopy (FESEM) showed that MMSNs had a uniform spherical morphology with a diameter of 19 nm and a negative surface charge. Elesclomol was successfully encapsulated in the open porous structure of the nanocarrier. The encapsulation efficiency (EE) and drug loading capacity (LC) were about 88% and 39%, respectively. Moreover, the prepared Au-ELC-MMSN-NH2 displayed pH responsive and sustained drug release within 96 h. Targeted nano-delivery systems were prepared with a final diameter of 89 nm and a negative surface charge. The MTT assay revealed that the targeted nano-delivery system induced highly effective cytotoxicity on colorectal cancer cells-expressing EpCAM aptamer (HT-29) compared to the CHO cells. This engineered nano-platform is a promising elesclomol replacement therapy for colorectal cancer. However, further experiments are required before it can be practiced in the clinic.

منابع و مأخذ:

Arkaban H, Jaberi J, Bahramifar A, Emameh RZ, Farnoosh G, Taheri RA, et al. Fabrication of Fe (III)-Doped Mesoporous Silica Nanoparticles as Biocompatible and Biodegradable Theranostic System for Remdesivir Delivery and MRI Contrast Agent. Inorganic Chemistry Communications. 2023:110398. doi: org/10.1016/j.inoche.2023.110398

[2] Babaei M, Abnous K, Taghdisi SM, Amel Farzad S, Peivandi MT, Ramezani M, et al. Synthesis of theranostic epithelial cell adhesion molecule targeted mesoporous silica nanoparticle with gold gatekeeper for hepatocellular carcinoma. Nanomedicine. 2017;12(11):1261-79. doi: org/10.2217/nnm-2017-0028

[3] Barui S, Cauda V. Multimodal decorations of mesoporous silica nanoparticles for improved cancer therapy. Pharmaceutics. 2020;12(6):527. doi: org/10.3390/pharmaceutics12060527

[4] Buccarelli M, D’Alessandris QG, Matarrese P, Mollinari C, Signore M, Cappannini A, et al. Elesclomol-induced increase of mitochondrial reactive oxygen species impairs glioblastoma stem-like cell survival and tumor growth. Journal of Experimental & Clinical Cancer Research. 2021;40:1-17. doi: org/10.3390/cancers14246193

[5] Chen S, Sun L, Koya K, Tatsuta N, Xia Z, Korbut T, et al. Syntheses and antitumor activities of N′ 1, N′ 3-dialkyl-N′ 1, N′ 3-di-(alkylcarbonothioyl) malonohydrazide: The discovery of elesclomol. Bioorganic & medicinal chemistry letters. 2013;23(18):5070-6. doi: org/10.1016/j.bmcl.2013.07.032

[6] Cheng Y-J, Qin S-Y, Ma Y-H, Chen X-S, Zhang A-Q, Zhang X-Z. Super-pH-sensitive mesoporous silica nanoparticle-based drug delivery system for effective combination cancer therapy. ACS Biomaterials Science & Engineering. 2019;5(4):1878-86. doi: org/10.1021/acsbiomaterials.9b00099

[7] Esfahani MKM, Alavi SE, Cabot PJ, Islam N, Izake EL. PEGylated Mesoporous Silica Nanoparticles (MCM-41): A promising carrier for the targeted delivery of fenbendazole into prostrate cancer cells. Pharmaceutics. 2021;13(10):1605. doi: org/10.3390/pharmaceutics14081579

[8] Farjadian F, Roointan A, Mohammadi-Samani S, Hosseini M. Mesoporous silica nanoparticles: synthesis, pharmaceutical applications, biodistribution, and biosafety assessment. Chemical Engineering Journal. 2019;359:684-705. doi: org/10.1016/j.cej.2018.11.156

[9] Feng L, Dong Z, Tao D, Zhang Y, Liu Z. The acidic tumor microenvironment: a target for smart cancer nano-theranostics. National Science Review. 2018;5(2):269-86. doi: org/10.1093/nsr/nwx062

[10] Fu Z, Xiang J. Aptamers, the nucleic acid antibodies, in cancer therapy. International Journal of Molecular Sciences. 2020;21(8):2793. doi: org/10.3390/ijms21239123

[11] Gires O, Pan M, Schinke H, Canis M, Baeuerle PA. Expression and function of epithelial cell adhesion molecule EpCAM: where are we after 40 years? Cancer and Metastasis Reviews. 2020;39:969-87. doi: org/10.1007/s10555-020-09898-3

[12] He K, Li J, Shen Y, Yu Y. pH-Responsive polyelectrolyte coated gadolinium oxide-doped mesoporous silica nanoparticles (Gd₂O₃@MSNs) for synergistic drug delivery and magnetic resonance imaging enhancement. Journal of Materials Chemistry B. 2019;7(43):6840-54. doi: org/10.1039/C8TA11172C

[13] Hedley D, Shamas-Din A, Chow S, Sanfelice D, Schuh AC, Brandwein JM, et al. A phase I study of elesclomol sodium in patients with acute myeloid leukemia. Leukemia & lymphoma. 2016;57(10):2437-40. doi: org/10.3390/biomedicines9080852

[14] Iranpour S, Bahrami AR, Nekooei S, Matin MM. Improving anti-cancer drug delivery performance of magnetic mesoporous silica nanocarriers for more efficient colorectal cancer therapy. Journal of Nanobiotechnology. 2021;19(1):1-22. doi: org/10.1186/s12951-021-01056-3

[15] Iranpour S, Bahrami AR, Saljooghi AS, Matin MM. Application of smart nanoparticles as a potential platform for effective colorectal cancer therapy. Coordination Chemistry Reviews. 2021;442:213949. doi: org/10.1016/j.ccr.2021.213949

[16] Kato Y, Ozawa S, Miyamoto C, Maehata Y, Suzuki A, Maeda T, et al. Acidic extracellular microenvironment and cancer. Cancer cell international. 2013;13:1-8. doi: org/10.1186/1475-2867-13-89

[17] Keshavarz H, Khavandi A, Alamolhoda S, Naimi-Jamal MR. pH-Sensitive magnetite mesoporous silica nanocomposites for controlled drug delivery and hyperthermia. RSC advances. 2020;10(64):39008-16. doi: org/10.1039/D0RA06916G

[18] Kirshner JR, He S, Balasubramanyam V, Kepros J, Yang C-Y, Zhang M, et al. Elesclomol induces cancer cell apoptosis through oxidative stress. Molecular cancer therapeutics. 2008;7(8):2319-27. doi: org/10.1158/1535-7163.MCT-08-0298

[19] Koohi Moftakhari Esfahani M, Alavi SE, Cabot PJ, Islam N, Izake EL. Application of mesoporous silica nanoparticles in cancer therapy and delivery of repurposed anthelmintics for cancer therapy. Pharmaceutics. 2022;14(8):1579. doi: org/10.3390/pharmaceutics14081579

[20] Li S-D, Huang L. Stealth nanoparticles: high density but sheddable PEG is a key for tumor targeting. Journal of controlled release: official journal of the Controlled Release Society. 2010;145(3):178.  doi: org/10.1016/j.jconrel.2010.03.016

[21] Li Y, Duo Y, Bi J, Zeng X, Mei L, Bao S, et al. Targeted delivery of anti-miR-155 by functionalized mesoporous silica nanoparticles for colorectal cancer therapy. International journal of nanomedicine. 2018;13:1241. doi: org/10.2147/IJN.S158290

[22] Liu C-M, Chen G-B, Chen H-H, Zhang J-B, Li H-Z, Sheng M-X, et al. Cancer cell membrane-cloaked mesoporous silica nanoparticles with a pH-sensitive gatekeeper for cancer treatment. Colloids and Surfaces B: Biointerfaces. 2019;175:477-86. doi: org/10.1016/j.colsurfb.2018.12.038

[23] Liu C-M, Chen G-B, Lin L-H, Zhang J-B, Guo S-M, Sheng M-X. Mesoporous silica nanoparticles with surface transformation ability for prostate cancer treatment. Colloids and Surfaces A: Physicochemical and Engineering Aspects. 2021;621:126592. doi: org/10.1016/j.colsurfa.2021.126592

[24] Modica-Napolitano JS, Bharath LP, Hanlon AJ, Hurley LD. The anticancer agent elesclomol has direct effects on mitochondrial bioenergetic function in isolated mammalian mitochondria. Biomolecules. 2019;9(8):298. doi: org/10.3390/biom9080298

[25] Mohammed A, Reza A, Shokooh Saljooghi A. Using magnetic mesoporous silica nanoparticles armed with EpCAM aptamer as an efficient platform for specific delivery of 5-fluorouracil to colorectal cancer cells. Frontiers in Bioengineering and Biotechnology. 2023;10. doi: org/10.3389/fbioe.2022.1095837

[26] Nagai M, Vo NH, Ogawa LS, Chimmanamada D, Inoue T, Chu J, et al. The oncology drug elesclomol selectively transports copper to the mitochondria to induce oxidative stress in cancer cells. Free Radical Biology and Medicine. 2012;52(10):2142-50. doi: org/10.1016/j.freeradbiomed.2012.03.017

[27] O'Day SJ, Eggermont AM, Chiarion-Sileni V, Kefford R, Grob JJ, Mortier L, et al. Final results of phase III SYMMETRY study: randomized, double-blind trial of elesclomol plus paclitaxel versus paclitaxel alone as treatment for chemotherapy-naive patients with advanced melanoma. Journal of Clinical Oncology. 2013;31(9):1211-8. doi: org/10.1200/JCO.2012.44.5585

[28] Olivas A, Price RS. Obesity, inflammation, and advanced prostate cancer. Nutrition and Cancer. 2021;73(11-12):2232-48. doi: org/10.1080/01635581.2020.1856889

[29] She X, Chen L, Velleman L, Li C, Zhu H, He C, et al. Fabrication of high specificity hollow mesoporous silica nanoparticles assisted by Eudragit for targeted drug delivery. Journal of Colloid and Interface Science. 2015;445:151-60. doi: org/10.1016/j.jcis.2014.12.053

[30] Siegel RL, Miller KD, Wagle NS, Jemal A. Cancer statistics, 2023. CA: a cancer journal for clinicians. 2023;73(1):17-48. doi: org/10.3322/caac.21763

[31] Su S, M Kang P. Recent advances in nanocarrier-assisted therapeutics delivery systems. Pharmaceutics. 2020;12(9):837. doi: org/10.3390/pharmaceutics12090837

[32] Tiburcius S, Krishnan K, Jose L, Patel V, Ghosh A, Sathish C, et al. Egg-yolk core–shell mesoporous silica nanoparticles for high doxorubicin loading and delivery to prostate cancer cells. Nanoscale. 2022;14(18):6830-45. doi: org/10.1039/D2NR00783E

[33] Torabi M, Aghanejad A, Savadi P, Barzegari A, Omidi Y, Barar J. Fabrication of mesoporous silica nanoparticles for targeted delivery of sunitinib to ovarian cancer cells. BioImpacts. 2023. doi: org/10.34172/bi.2023.25298

[34] Torabi M, Aghanejad A, Savadi P, Barzegari A, Omidi Y, Barar J. Targeted Delivery of Sunitinib by MUC-1 Aptamer-Capped Magnetic Mesoporous Silica Nanoparticles. Molecules. 2023;28(1):411. doi: org/10.3390/molecules28010411

[35] Tsvetkov P, Coy S, Petrova B, Dreishpoon M, Verma A, Abdusamad M, et al. Copper induces cell death by targeting lipoylated TCA cycle proteins. Science. 2022;375(6586):1254-61. doi: org/10.1126/science.abf0529

[36] Wong HN, Lewies A, Haigh M, Viljoen JM, Wentzel JF, Haynes RK, et al. Anti-melanoma activities of artemisone and prenylated amino-artemisinins in combination with known anticancer drugs. Frontiers in Pharmacology. 2020;11:558894. doi: org/10.3389/fphar.2020.558894

[37] Wu J. The enhanced permeability and retention (EPR) effect: The significance of the concept and methods to enhance its application. Journal of Personalized Medicine. 2021;11(8):771. doi: org/10.3390/jpm11080771

[38] Xu Y, Zhao H, Hou J. Correlation between overexpression of EpCAM in prostate tissues and genesis of androgen-dependent prostate cancer. Tumor Biology. 2014;6695:700-35. doi: org/10.1007/s13277-014-1892-2

[39] Zhang B-b, Chen X-j, Fan X-d, Zhu J-j, Wei Y-h, Zheng H-s, et al. Lipid/PAA-coated mesoporous silica nanoparticles for dual-pH-responsive codelivery of arsenic trioxide/paclitaxel against breast cancer cells. Acta Pharmacologica Sinica. 2021;42(5):832-42. doi: org/10.1038/s41401-021-00648-x

[40] Zhang Y, Zhi Z, Jiang T, Zhang J, Wang Z, Wang S. Spherical mesoporous silica nanoparticles for loading and release of the poorly water-soluble drug telmisartan. Journal of Controlled Release. 2010;145(3):257-63. doi: org/10.1016/j.jconrel.2010.04.029

[41] Zheng P, Zhou C, Lu L, Liu B, Ding Y. Elesclomol: a copper ionophore targeting mitochondrial metabolism for cancer therapy. Journal of Experimental & Clinical Cancer Research. 2022;41(1):1-13. doi: org/10.1186/s13046-022-02485-0

[42] Zhou J, Rossi J. Aptamers as targeted therapeutics: current potential and challenges. Nature reviews Drug discovery. 2017;16(3):181-202. doi: org/10.1038/nrd.2016.199

[43] Zhu D, Hu C, Liu Y, Chen F, Zheng Z, Wang X. Enzyme-/redox-responsive mesoporous silica nanoparticles based on functionalized dopamine as nanocarriers for cancer therapy. ACS Omega. 2019;4(4):6097-105. doi: org/10.1021/acsomega.8b02537

[44] Kamil Mohammad Al-Mosawi A, Bahrami AR, Nekooei S, Saljooghi AS, Matin MM. Using magnetic mesoporous silica nanoparticles armed with EpCAM aptamer as an efficient platform for specific delivery of 5-fluorouracil to colorectal cancer cells. Frontiers in Bioengineering and Biotechnology. 2023;14(1):33-49 doi: org/10.61186/JCT.14.1.33