Gadoterate meglumine - anionic linear globular dendrimer second generation: A novel nano sized theranostic contrast agent

Document Type : Research Paper

Authors

1 Department of Radiopharmacy, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran

2 Department of Medicinal Chemistry, School of Pharmacy, Ardabil University of Medical Sciences, Ardabil, Iran

Abstract

Objective(s): Cancer is known as one of the most life-threatening diseases in the world. Early diagnosis of cancer may significantly increase the chance of effective treatment. In the recent years, the importance of medical imaging usage has been increased to identify cancer’s nature and pattern of growth in order to provide the most advantageous treatment approaches for cancer tumors. Magnetic resonance imaging is an efficient non-invasive tool for early diagnosis of cancer which provides clear scans of various tissues without radiation. Contrast Agents such as Gadoterate Meglumine enhance contrast MR imaging and provide imaging from inside the cells without entering them.
Materials and Methods: In this study, Gadoterate Meglumine nano-sized anionic linear globular dendrimer second generation was first synthesized and then qualitative and quantitative methods were carried out to ensure the proper synthesis and to assess the toxicity of the compound. Once the non-toxicity of the chemical was ensured, in vivo MR imaging studies was performed to test the impact of the synthesized compound on the resolution of image.
Results: The result obtained from this study demonstrated that the attachment of Gadolinium (III) to a nano dendrimer reduces its cytotoxicity and also improved resolution of image. In this research, Gadoterate Meglumine nano-sized anionic linear globular dendrimer second generation was effectively able to enter the cells while showing low cytotoxicity in the normal cells and moderate cytotoxicity on cancer cells.
Conclusion: Therefore, ALGDG2-GM could be introduced as a novel, safe, effective and promising nano-sized theranostic contrast agent candidate.

Keywords


1. Stewart BW, Bray F, Forman D, Ohgaki H, Straif K, Ullrich A, Wild CP. Cancer prevention as part of precision medicine: ‘plenty to be done’. Carcinogenesis. 2016;37(1):2-9.
2.    Siegel RL, Miller KD, Jemal A. Cancer Statistics. CA Cancer J Clin. 2017;67(1):7-30.
3.    Anand P, Kunnumakkara AB, Sundaram C, Harikumar KB, Tharakan ST, Lai OS, Sung B, Aggarwal BB. Cancer is a preventable disease that requires major lifestyle changes. Pharm Res. 2008; 25(9):2097-2116.
4.    Cibiel A, Pestourie C, Ducongé F. In vivo uses of aptamers selected against cell surface biomarkers for therapy and molecular imaging. Biochimie. 2012;94(7):1595-1606.
5.    Anderson CJ, Lewis JS. Current status and future challenges for molecular imaging. Philos Trans A Math Phys Eng Sci. 2017;375(2107):20170023.
6.    Wu M, Shu J. Multimodal Molecular Imaging: Current Status and Future Directions. Contrast Media Mol Imaging. 2018; 2018:1382183.
7.    Hermann P, Kotek J, Kubícek V, Lukes I. Gadolinium(III) complexes as MRI contrast agents: ligand design and properties of the complexes. Dalton Trans. 2008; (23): 3027-47.
8.    Rogosnitzky M, Branch S. Gadolinium-based contrast agent toxicity: a review of known and proposed mechanisms. Biometals. 2016;29(3):365-376.
9.    Zhou Z, Lu ZR. Gadolinium-based contrast agents for magnetic resonance cancer imaging. Wiley Interdiscip Rev Nanomed Nanobiotechnol. 2013;5(1):1-18.
10.    Perazella MA. Current status of gadolinium toxicity in patients with kidney disease. Clin J Am Soc Nephrol. 2009; 4(2):461-469.
11.    Kim J, Lee N, Hyeon T. Recent development of nanoparticles for molecular imaging. Philos Trans A Math Phys Eng Sci. 2017;375(2107):20170022.
12.    Mohammadi E, Amanlou M, Ebrahimi SES, Hamedani MP, Mahrooz A, Mehravi B, Emami BA, Aghasadeghi MR, Bitarafan AR, Pouraliakbar HR, Ardestani MS. Cellular uptake, imaging and pathotoxicological studies of a novel Gd [III]–DO3A-butrol nano-formulation. Rsc Advances. 2014; 4(86): 45984-45994.
13.    Naseri N, Ajorlou E, Asghari F, Pilehvar-Soltanahmadi Y. An update on nanoparticle-based contrast agents in medical imaging. Artif Cells Nanomed Biotechnol. 2018;46(6): 1111-1121.
14.    Patra JK, Das G, Fraceto LF, Campos EVR, Rodriguez-Torres MDP, Acosta-Torres LS, Diaz-Torres LA, Grillo R, Swamy MK, Sharma S, Habtemariam S, Shin HS. Nano based drug delivery systems: recent developments and future prospects. J Nanobiotechnology. 2018;16(1):71.
15.    Din FU, Aman W, Ullah I, Qureshi OS, Mustapha O, Shafique S, Zeb A. Effective use of nanocarriers as drug delivery systems for the treatment of selected tumors. Int J Nanomedicine. 2017;12:7291-7309.
16.    Ding L, Lyu Z, Dhumal D, Kao CL, Bernard M, Peng L. Dendrimer-based magnetic resonance imaging agents for brain cancer. Sci China Mater. 2018;61(11):1420-1443.
17.    Svenson S, Tomalia DA. Dendrimers in biomedical applications--reflections on the field. Adv Drug Deliv Rev. 2005;57(15):2106-2129.
18.    Gillies ER, Fréchet JM. Dendrimers and dendritic polymers in drug delivery. Drug Discov Today. 2005;10(1):35-43.
19.    Lo ST, Kumar A, Hsieh JT, Sun X. Dendrimer nanoscaffolds for potential theranostics of prostate cancer with a focus on radiochemistry. Mol Pharm. 2013;10(3):793-812.
20.    Zhu Y, Liu C, Pang Z. Dendrimer-Based Drug Delivery Systems for Brain Targeting. Biomolecules. 2019;9(12): 790.
21.    Singh AP, Biswas A, Shukla A, Maiti P. Targeted therapy in chronic diseases using nanomaterial-based drug delivery vehicles. Signal Transduct Target Ther. 2019;4:33.
22.    Sandoval-Yañez C, Castro Rodriguez C. Dendrimers: Amazing Platforms for Bioactive Molecule Delivery Systems. Materials (Basel). 2020;13(3):570.
23.    Fana M, Gallien J, Srinageshwar B, Dunbar GL, Rossignol J. PAMAM Dendrimer Nanomolecules Utilized as Drug Delivery Systems for Potential Treatment of Glioblastoma: A Systematic Review. Int J Nanomedicine. 2020;15:2789-2808.
24.    Dong Q, Yang H, Wan C, Zheng D, Zhou Z, Xie S, Xu L, Du J, Li F. Her2-Functionalized Gold-Nanoshelled Magnetic Hybrid Nanoparticles: a Theranostic Agent for Dual-Modal Imaging and Photothermal Therapy of Breast Cancer. Nanoscale Res Lett. 2019;14(1):235.
25.    Ray S, Li Z, Hsu CH, Hwang LP, Lin YC, Chou PT, Lin YY. Dendrimer- and copolymer-based nanoparticles for magnetic resonance cancer theranostics. Theranostics. 2018;8(22):6322-6349.
26.    Mohammadzadeh P, Cohan RA, Ghoreishi SM, Bitarafan-Rajabi A, Ardestani MS. AS1411 Aptamer-Anionic Linear Globular Dendrimer G2-Iohexol Selective Nano-Theranostics. Sci Rep. 2017;7(1):11832.
27.    Mirzaei M, Mohagheghi M, Shahbazi-Gahrouei D, Khatami A. Novel Nanosized Gd3+-ALGD-G2-C595: In vivo Dual Selective MUC-1 Positive Tumor Molecular MR Imaging and Therapeutic Agent. J Nanomed Nanotechol. 2012; 3:147.
28.    Wängler C, Moldenhauer G, Eisenhut M, Haberkorn U, Mier W. Antibodydendrimer conjugates: the number, not the size of the dendrimers, determines the immunoreactivity. Bioconjug Chem. 2008;19 813-820.
29.    Turyanskaya A, Rauwolf M, Pichler V, Simon R, Burghammer M, Fox OJL, Sawhney K, Hofstaetter JG, Roschger A, Roschger P, Wobrauschek P, Streli C. Detection and imaging of gadolinium accumulation in human bone tissue by micro- and submicro-XRF. Sci Rep. 2020;10(1):6301.
30.    Jeong Y, Hwang HS, Na K. Theranostics and contrast agents for magnetic resonance imaging. Biomater Res. 2018; 22:20.
31.    Assadi A, Najafabadi VS, Shandiz SA, Boroujeni AS, Ashrafi S, Vaziri AZ, Ghoreishi SM, Aghasadeghi MR, Ebrahimi SE, Pirali-Hamedani M, Ardestani MS. Novel chlorambucil-conjugated anionic linear-globular PEG-based second-generation dendrimer: in vitro/in vivo improved anticancer activity. Onco Targets Ther. 2016;9:5531-5543.
32.    Abbasi E, Aval SF, Akbarzadeh A, Milani M, Nasrabadi HT, Joo SW, Hanifehpour Y, Nejati-Koshki K, Pashaei-Asl R. Dendrimers: synthesis, applications, and properties. Nanoscale Res Lett. 2014;9(1):247.
33.    Nanjwade BK, Bechra HM, Derkar GK, Manvi FV, Nanjwade VK. Dendrimers: emerging polymers for drug-delivery systems. Eur J Pharm Sci. 2009;38(3):185-196.