Targeted delivery of doxorubicin and therapeutic FOXM1 aptamer to tumor cells using gold nanoparticles modified with AS1411 and ATP aptamers

Document Type : Original Article

Authors

1 School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran

2 Pharmaceutical Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran

3 Department of Chemistry and Biomolecular Sciences, University of Ottawa, 10 Marie-Curie, Ottawa, ON K1N 6N5, Canada

4 Department of Medicinal Chemistry, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran

5 Targeted Drug Delivery Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran

6 Department of Pharmaceutical Biotechnology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran

Abstract

Objective(s): A targeted delivery platform was prepared to co-deliver both doxorubicin (Dox) as an anticancer drug and FOXM1 aptamer as a therapeutic substance to breast cancer cells (4T1 and MCF-7) to reduce Dox side effects and increase its therapeutic efficacy. The targeted system (AuNPs-AFPA) consisted of FOXM1 aptamer, AS1411 aptamer (targeting oligonucleotide), ATP aptamer, and gold nanoparticles (AuNPs) as a carrier.
Materials and Methods: AuNPs were synthesized by reduction of HAuCl4. Next, after pegylation of ATP aptamer, FOXM1 aptamer-PEGylated ATP aptamer conjugate (FPA) was prepared. Then, the AS1411 aptamer and FPA were exposed to the AuNPs surface through their thiol groups. Subsequently, Dox was loaded into the complex to form a targeted therapeutic complex.
Results: The data of the MTT assay displayed that the targeted complex could remarkably reduce cell viability rate in target cells due to the overexpression of nucleolin on their cell membranes compared to nontarget cells, showing the targeting ability of AuNPs-AFPA-Dox. The in vivo antitumor effect confirmed that AuNPs-AFPA-Dox was capable of remarkably diminishing tumor growth relative to the free Dox in mice bearing 4T1 tumor cells. 
Conclusion: The results confirmed that the targeted system improved the therapeutic effect by loading high amounts of Dox alongside the presence of the therapeutic effect of FOXM1 aptamer. Finally, it can be concluded that AuNPs-AFPA-Dox by enhancing antitumor effectiveness and reducing toxicity toward non-target cells, can be used potentially as an effective strategy for the treatment of breast cancer.v

Keywords

Main Subjects


1. Barzaman K, Karami J, Zarei Z, Hosseinzadeh A, Kazemi MH, Moradi-Kalbolandi S, et al. Breast cancer: Biology, biomarkers, and treatments. Int Immunopharmacol 2020; 84:106535.
2. Abdalkareem Jasim S, Zedan Khalaf O, Hamoud Alshahrani S, Hachem K, Ziyadullaev S, Turki Jalil A, et al. An in vitro investigation of the apoptosis-inducing activity of corosolic acid in breast cancer cells. Iran J Basic Med Sci 2023; 26:453-460.
3. Atlan M, Neman J. Targeted transdermal delivery of curcumin for breast cancer prevention. Int J Environ Res Public Health 2019; 16:4949.
4. Turato C, Balasso A, Carloni V, Tiribelli C, Mastrotto F, Mazzocca A, et al. New molecular targets for functionalized nanosized drug delivery systems in personalized therapy for hepatocellular carcinoma. J Control Release 2017; 268:184-197.
5. Ghanghoria R, Kesharwani P, Tekade RK, Jain NK. Targeting luteinizing hormone-releasing hormone: A potential therapeutics to treat gynecological and other cancers. J Control Release 2018; 269:277-301.
6. Turato C, Balasso A, Carloni V, Tiribelli C, Mastrotto F, Mazzocca A, et al. New molecular targets for functionalized nanosized drug delivery systems in personalized therapy for hepatocellular carcinoma. J Control Release 2017; 268:184-197.
7. Liu P, Zhang R, Yu W, Ye Y, Cheng Y, Han L, et al. FGF1 and IGF1-conditioned 3D culture system promoted the amplification and cancer stemness of lung cancer cells. Biomaterials 2017; 149:63-76.
8. Wang Z, Deng X, Ding J, Zhou W, Zheng X, Tang G. Mechanisms of drug release in pH-sensitive micelles for tumour targeted drug delivery system: A review. Int J Pharm 2018; 535:253-260.
9. Jalalian SH, Taghdisi SM, Shahidi Hamedani N, Kalat SA, Lavaee P, Zandkarimi M, et al. Epirubicin loaded super paramagnetic iron oxide nanoparticle-aptamer bioconjugate for combined colon cancer therapy and imaging in vivo. Eur J Pharm Sci 2013; 50:191-197.
10. Yung BC, Li J, Zhang M, Cheng X, Li H, Yung EM, et al. Lipid nanoparticles composed of quaternary amine-tertiary amine cationic lipid combination (QTsome) for therapeutic delivery of antimir-21 for lung cancer. Mol Pharm 2016; 13:653-662.
11. Farhangfar S, Fesahat F, Zare-Zardini H, Dehghan-Manshadi M, Zare F, Mirsmaeili SM, et al. In vivo study of anticancer activity of ginsenoside Rh2-containing arginine-reduced graphene in a mouse model of breast cancer. Iran J Basic Med Sci 2022; 25:1442-1451.
12. Khan A, Rashid R, Murtaza G, Zahra A. Gold nanoparticles: synthesis and applications in drug delivery. Trop J Pharm Res 2014; 13:1169-1177.
13. Danesh NM, Lavaee P, Ramezani M, Abnous K, Taghdisi SM. Targeted and controlled release delivery of daunorubicin to T-cell acute lymphoblastic leukemia by aptamer-modified gold nanoparticles. Int J Pharm 2015; 489:311-317.
14. Kumari P, Ghosh B, Biswas S. Nanocarriers for cancer-targeted drug delivery. J drug targeting 2016; 24:179-191.
15. Pishavar E, Yazdian-Robati R, Abnous K, Hashemi M, Ebrahimian M, Feizpour R, et al. Aptamer-functionalized mesenchymal stem cells-derived exosomes for targeted delivery of SN38 to colon cancer cells. Iran J Basic Med Sci 2023; 26:388-394.
16. Bayat P, Nosrati R, Alibolandi M, Rafatpanah H, Abnous K, Khedri M, et al. SELEX methods on the road to protein targeting with nucleic acid aptamers. Biochimie 2018; 154:132-155.
17. Tang X, Wang Y-S, Xue J-H, Zhou B, Cao J-X, Chen S-H, et al. A novel strategy for dual-channel detection of metallothioneins and mercury based on the conformational switching of functional chimera aptamer. J Pharm Biomed Anal 2015; 107:258-264.
18. Abnous K, Danesh NM, Ramezani M, Charbgoo F, Bahreyni A, Taghdisi SM. Targeted delivery of doxorubicin to cancer cells by a cruciform DNA nanostructure composed of AS1411 and FOXM1 aptamers. Expert Opin Drug Deliv 2018; 15:1045-1052.
19. Xiang Q, Tan G, Jiang X, Wu K, Tan W, Tan Y. Suppression of FOXM1 transcriptional activities via a single-stranded DNA aptamer generated by SELEX. Sci Rep 2017; 7:45377.
20. Barati Farimani A, Dibaeinia P, Aluru NR. DNA origami–graphene hybrid nanopore for DNA detection. ACS Appl Mater Interfaces 2017; 9:92-100.
21. Abnous K, Danesh NM, Ramezani M, Yazdian-Robati R, Alibolandi M, Taghdisi SM. A novel chemotherapy drug-free delivery system composed of three therapeutic aptamers for the treatment of prostate and breast cancers in vitro and in vivo. Nanomedicine 2017; 13:1933-1940.
22. Jiang Q, Zhao S, Liu J, Song L, Wang ZG, Ding B. Rationally designed DNA-based nanocarriers. Adv Drug Deliv Rev 2019; 147:2-21.
23. Dapić V, Bates PJ, Trent JO, Rodger A, Thomas SD, Miller DM. Antiproliferative activity of G-quartet-forming oligonucleotides with backbone and sugar modifications. Biochemistry 2002; 41:3676-3685.
24. Dam DH, Lee JH, Sisco PN, Co DT, Zhang M, Wasielewski MR, et al. Direct observation of nanoparticle-cancer cell nucleus interactions. ACS Nano 2012; 6:3318-3326.
25. Yaghoobi E, Zavvar T, Ramezani M, Alibolandi M, Oskuei S, Zahiri M, et al. A multi-storey DNA nanostructure containing doxorubicin and AS1411 aptamer for targeting breast cancer cells. J Drug Targeting 2022:1-11.
26. Li F, Lu J, Liu J, Liang C, Wang M, Wang L, et al. A water-soluble nucleolin aptamer-paclitaxel conjugate for tumor-specific targeting in ovarian cancer. Nat Commun 2017; 8:1390.
27. Taghdisi SM, Danesh NM, Ramezani M, Yazdian-Robati R, Abnous K. A Novel AS1411 aptamer-based three-way junction pocket DNA nanostructure loaded with doxorubicin for targeting cancer cells in vitro and in vivo. Mol Pharm 2018; 15:1972-1978.
28. Yaghoobi E, Shojaee S, Ramezani M, Alibolandi M, Charbgoo F, Nameghi MA, et al. A novel targeted co-delivery system for transfer of epirubicin and antimiR-10b into cancer cells through a linear DNA nanostructure consisting of FOXM1 and AS1411 aptamers. J Drug Delivery Sci Technol 2021; 63:102521.
29. Halasi M, Gartel AL. Suppression of FOXM1 sensitizes human cancer cells to cell death induced by DNA-damage. PLoS One 2012; 7:e31761.
30. Urata H, Nomura K, Wada S, Akagi M. Fluorescent-labeled single-strand ATP aptamer DNA: chemo- and enantio-selectivity in sensing adenosine. Biochem Biophys Res Commun 2007; 360:459-463.
31. Sameiyan E, Bagheri E, Dehghani S, Ramezani M, Alibolandi M, Abnous K, et al. Aptamer-based ATP-responsive delivery systems for cancer diagnosis and treatment. Acta Biomater 2021; 123:110-122.
32. Mo R, Jiang T, DiSanto R, Tai W, Gu Z. ATP-triggered anticancer drug delivery. Nat Commun 2014; 5:3364.
33. Zhou F, Wang P, Peng Y, Zhang P, Huang Q, Sun W, et al. Molecular engineering-based aptamer–drug conjugates with accurate tunability of drug ratios for drug combination targeted cancer therapy. Angew Chem Int Ed 2019; 58:11661-11665.
34. Storhoff JJ, Elghanian R, Mucic RC, Mirkin CA, Letsinger RL. One-pot colorimetric differentiation of polynucleotides with single base imperfections using gold nanoparticle probes. J Am Chem Soc 1998; 120:1959-1964.
35. Danesh NM, Lavaee P, Ramezani M, Abnous K, Taghdisi SM. Targeted and controlled release delivery of daunorubicin to T-cell acute lymphoblastic leukemia by aptamer-modified gold nanoparticles. Int J Pharm 2015; 489:311-317.
36. Abnous K, Danesh NM, Ramezani M, Alibolandi M, Bahreyni A, Lavaee P, et al. A smart ATP-responsive chemotherapy drug-free delivery system using a DNA nanostructure for synergistic treatment of breast cancer in vitro and in vivo. J Drug Targeting 2020; 28:852-859.
37. Khademi Z, Lavaee P, Ramezani M, Alibolandi M, Abnous K, Taghdisi SM. Co-delivery of doxorubicin and aptamer against Forkhead box M1 using chitosan-gold nanoparticles coated with nucleolin aptamer for synergistic treatment of cancer cells. Carbohydr Polym 2020; 248:116735.
38. Dassie JP, Giangrande PH. Current progress on aptamer-targeted oligonucleotide therapeutics. Ther Deliv 2013; 4:1527-1546.
39. Nuzzo S, Catuogno S, Capuozzo M, Fiorelli A, Swiderski P, Boccella S, et al. Axl-targeted delivery of the oncosuppressor mir-137 in non-small-cell lung cancer. Mol Ther Nucleic Acids 2019; 17:256-263.
40. Kopeckova K, Eckschlager T, Sirc J, Hobzova R, Plch J, Hrabeta J, et al. Nanodrugs used in cancer therapy. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 2019; 163:122-131.
41. Morales-Cruz M, Delgado Y, Castillo B, Figueroa CM, Molina AM, Torres A, et al. Smart targeting to improve cancer therapeutics. Drug Des Devel Ther 2019; 13:3753-3772.
42. Li X, Wang L, Fan Y, Feng Q, Cui F-z. Biocompatibility and toxicity of nanoparticles and nanotubes. J Nanomater 2012; 2012:548389.
43. Shukla R, Bansal V, Chaudhary M, Basu A, Bhonde RR, Sastry M. Biocompatibility of gold nanoparticles and their endocytotic fate inside the cellular compartment: A microscopic overview. Langmuir 2005; 21:10644-10654.
44. Gopinath K, Gowri S, Karthika V, Arumugam A. Green synthesis of gold nanoparticles from fruit extract of terminalia arjuna, for the enhanced seed germination activity of Gloriosa superba. J Nanostruct Chem 2014; 4:115.
45. Gopinath SC, Lakshmipriya T, Awazu K. Colorimetric detection of controlled assembly and disassembly of aptamers on unmodified gold nanoparticles. Biosens Bioelectron 2014; 51:115-123.
46. Liu J, Guan Z, Lv Z, Jiang X, Yang S, Chen A. Improving sensitivity of gold nanoparticle based fluorescence quenching and colorimetric aptasensor by using water resuspended gold nanoparticle. Biosens Bioelectron 2014; 52:265-270.
47. Chung CH, Kim JH, Jung J, Chung BH. Nuclease-resistant DNA aptamer on gold nanoparticles for the simultaneous detection of Pb2+ and Hg2+ in human serum. Biosens Bioelectron 2013; 41:827-832.
48. Yehl K, Joshi JP, Greene BL, Dyer RB, Nahta R, Salaita K. Catalytic Deoxyribozyme-Modified Nanoparticles for RNAi-Independent Gene Regulation. ACS Nano 2012; 6:9150-9157.
49. Yazdian-Robati R, Ramezani M, Jalalian SH, Abnous K, Taghdisi SM. Targeted delivery of epirubicin to cancer cells by polyvalent aptamer system in vitro and in vivo. Pharm Res 2016; 33:2289-2297.
50. Bagalkot V, Farokhzad OC, Langer R, Jon S. An aptamer-doxorubicin physical conjugate as a novel targeted drug-delivery platform. Angew Chem Int Ed Engl 2006; 45:8149-8152.
51. Cheng W, Liang C, Wang X, Tsai HI, Liu G, Peng Y, et al. A drug-self-gated and tumor microenvironment-responsive mesoporous silica vehicle: “four-in-one” versatile nanomedicine for targeted multidrug-resistant cancer therapy. Nanoscale 2017; 9:17063-17073.
52. Porciani D, Tedeschi L, Marchetti L, Citti L, Piazza V, Beltram F, et al. Aptamer-mediated codelivery of doxorubicin and nf-κb decoy enhances chemosensitivity of pancreatic tumor cells. Mol Ther Nucleic Acids 2015; 4:e235.
53. Nejabat M, Mohammadi M, Abnous K, Taghdisi SM, Ramezani M, Alibolandi M. Fabrication of acetylated carboxymethylcellulose coated hollow mesoporous silica hybrid nanoparticles for nucleolin targeted delivery to colon adenocarcinoma. Carbohydr Polym 2018; 197:157-166.
54. Kalyanaraman B. Teaching the basics of the mechanism of doxorubicin-induced cardiotoxicity: Have we been barking up the wrong tree? Redox Biol 2020; 29:101394.