Generic placeholder image

Anti-Cancer Agents in Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 1871-5206
ISSN (Online): 1875-5992

Research Article

Preparation and Preliminary Evaluation of 68Ga-Acridine: An Attempt to Study the Potential of Radiolabeled DNA Intercalator as a PET Radiotracer for Tumor Imaging

Author(s): Subhajit Ghosh, Tapas Das*, Shishu K. Suman, Haladhar D. Sarma and Ashutosh Dash

Volume 20, Issue 13, 2020

Page: [1538 - 1547] Pages: 10

DOI: 10.2174/1871520620666200502002609

Price: $65

conference banner
Abstract

Introduction: Acridine is a well-known DNA intercalator and thereby gets easily inserted within DNA. As uncontrolled rapid cell division is one of the primary characteristics of the tumors, it is expected that acridine or its suitable derivatives will have preferential accumulation in the tumorous lesions. Therefore, an attempt was made to radiolabel an acridine derivative with 68Ga and study the potential of the 68Ga-acridine complex as a PET agent for tumor imaging.

Methods: 9-aminoacridine was coupled with p-NCS-benzyl-DOTA to render it suitable for labeling with 68Ga. The purified acridine-DOTA conjugate was radiolabeled with 68Ga, eluted from a 68Ge/68Ga radionuclide generator. Various radiolabeling parameters were optimized and the stability of the radiolabeled preparation was studied. The biological behavior of the 68Ga-acridine complex was studied both in vitro and in vivo using Raji cell line and fibrosarcoma tumor bearing Swiss mice, respectively.

Results: 68Ga-acridine complex was obtained with ~100% radiochemical purity under the optimized reaction conditions involving incubation of 2mg/mL of ligand at 100°C for 30 minutes. The complex maintained a radiochemical purity of >95% in normal saline and >65% in human blood serum at 3h post-incubation. In vitro cellular study showed (3.2±0.1)% uptake of the radiotracer in the Raji cells. Biodistribution study revealed significant tumor accumulation [(11.41±0.41)% injected activity in per gram] of the radiotracer within 1h postadministration along with uptake in other non-target organs such as, blood, liver, GIT kidney etc.

Conclusion: The present study indicates the potential of 68Ga-acridine as a PET agent for imaging of tumorous lesions. However, further detailed evaluation of the agent is warranted to explore its actual potential.

Keywords: Radiolabeled DNA intercalator, 68Ga-acridine, PET radiotracer, tumor imaging, fibrosarcoma, acridine-DOTA conjugate.

Graphical Abstract
[1]
https://www.who.int/news-room/fact-sheets/detail/cancer ( Accessed on: 10th September,. 2019).
[3]
https://www.who.int/cancer/detection/en/ (Accessed on: 10th September,. 2019).
[5]
Fukumoto, M. Single-photon agents for tumor imaging: 201Tl, 99mTc-MIBI, and 99mTc-tetrofosmin. Ann. Nucl. Med., 2004, 18(2), 79-95.
[http://dx.doi.org/10.1007/BF02985098] [PMID: 15195755]
[7]
Ghosh, S.; Das, T.; Sarma, H.D.; Dash, A. The potential of radiolabeled chemotherapeutics in tumor diagnosis: Preliminary investigations with 68Ga-gemcitabine. Drug Dev. Res., 2018, 79(3), 111-118.
[http://dx.doi.org/10.1002/ddr.21423] [PMID: 29380405]
[8]
Singh, H.; Singh, H.; Sharma, S.; Bedi, P.M.S. Chemotherapeutic potential of acridine analogs: An ample review. Heterocycles, 2015, 91(11), 2043-2085.
[http://dx.doi.org/10.3987/REV-15-826]
[9]
Mishra, B.B.; Kumar, D.; Singh, A.S.; Tripathi, R.P.; Tiwari, V.K. Ionic liquids-prompted synthesis of biologically relevant five- and six-membered heterocyclic skeletons: An update. In: Green synthetic approaches for biologically relevant heterocycles; Brahmachari, G., Ed.; Elsevier, 2015; pp. 437-493.
[10]
Chen, Y.L.; Lu, C.M.; Chen, I.L.; Tsao, L.T.; Wang, J.P. Synthesis and antiinflammatory evaluation of 9-anilinoacridine and 9-phenoxyacridine derivatives. J. Med. Chem., 2002, 45(21), 4689-4694.
[http://dx.doi.org/10.1021/jm020102v] [PMID: 12361395]
[11]
Gamage, S.A.; Spicer, J.A.; Atwell, G.J.; Finlay, G.J.; Baguley, B.C.; Denny, W.A. Structure-activity relationships for substituted bis(acridine-4-carboxamides): A new class of anticancer agents. J. Med. Chem., 1999, 42(13), 2383-2393.
[http://dx.doi.org/10.1021/jm980687m] [PMID: 10395479]
[12]
Kaya, M.; Yıldırır, Y.; Çelik, G.Y. Synthesis and antimicrobial activities of novel bisacridine-1,8-dione derivatives. Med. Chem. Res., 2011, 20(3), 293-298.
[http://dx.doi.org/10.1007/s00044-010-9321-6]
[13]
Tripathi, R.P.; Verma, S.S.; Pandey, J.; Agarwal, K.C.; Chaturvedi, V.; Manju, Y.K.; Srivastva, A.K.; Gaikwad, A.; Sinha, S. Search of antitubercular activities in tetrahydroacridines: Synthesis and biological evaluation. Bioorg. Med. Chem. Lett., 2006, 16(19), 5144-5147.
[http://dx.doi.org/10.1016/j.bmcl.2006.07.025] [PMID: 16870429]
[14]
Carole, D.G.; Michel, D.M.; Julien, C.; Florence, D.; Anna, N.; Séverine, J.; Gérard, D.; Pierre, T.D.; Jean-Pierre, G. Synthesis and antileishmanial activities of 4,5-di-substituted acridines as compared to their 4-mono-substituted homologues. Bioorg. Med. Chem., 2005, 13(19), 5560-5568.
[http://dx.doi.org/10.1016/j.bmc.2005.06.045] [PMID: 16081295]
[15]
Gupta, H.C.; Jaiswal, V. Synthesis and antiviral activity of some acridin-9-yl aryldithiocarbamates. Indian J. Heterocycl. Chem., 2010, 19(4), 409-410.
[16]
Srivastava, A.; Nizamuddin, A. Synthesis and fungicidal activity of some acridine derivatives. Indian J. Heterocycl. Chem., 2004, 13(3), 261-264.
[17]
Gensicka-Kowalewska, M.; Cholewiński, G.; Dzierzbicka, K. Recent developments in the synthesis and biological activity of acridine/acridone analogues. RSC Advances, 2017, 7(26), 15776-15804.
[http://dx.doi.org/10.1039/C7RA01026E]
[18]
[19]
Roesch, F.; Riss, P.J. The renaissance of the 68Ge/68Ga radionuclide generator initiates new developments in 68Ga radiopharmaceutical chemistry. Curr. Top. Med. Chem., 2010, 10(16), 1633-1668.
[http://dx.doi.org/10.2174/156802610793176738] [PMID: 20583984]
[20]
Rösch, F. Past, present and future of 68Ge/68Ga generators. Appl. Radiat. Isot., 2013, 76, 24-30.
[http://dx.doi.org/10.1016/j.apradiso.2012.10.012] [PMID: 23245638]
[21]
Mittal, S.; Bhadwal, M.; Chakraborty, S.; Sarma, H.D.; Banerjee, S.; Pillai, M.R.A. A novel concept of radiosynthesis of a 99mTc-labeled dimeric RGD peptide as a potential radiotracer for tumor imaging. Bioorg. Med. Chem. Lett., 2013, 23(6), 1808-1812.
[http://dx.doi.org/10.1016/j.bmcl.2013.01.036] [PMID: 23414841]
[22]
Bhadwal, M.; Das, T.; Dev Sarma, H.; Banerjee, S. Radiosynthesis and bioevaluation of 68Ga-labeled 5,10,15,20-tetra(4-methylpyridyl)-porphyrin for possible application as a PET radiotracer for tumor imaging. Mol. Imaging Biol., 2015, 17(1), 111-118.
[http://dx.doi.org/10.1007/s11307-014-0760-1] [PMID: 25037973]
[23]
Das, T.; Chakraborty, S.; Sarma, H.D.; Venkatesh, M.; Banerjee, S. Preparation of 166Ho-oxine-lipiodol and its preliminary bioevaluation for the potential application in therapy of liver cancer. Nucl. Med. Commun., 2009, 30(5), 362-367.
[http://dx.doi.org/10.1097/MNM.0b013e328329981a] [PMID: 19282794]
[24]
Goftar, M.K.; Kor, N.M.; Kor, Z.M. DNA intercalators and using them as anticancer drugs. Int. J. Adv. Biol. Biomed. Res., 2014, 2(3), 811-812.
[25]
Denny, W.A. DNA-intercalating ligands as anti-cancer drugs: prospects for future design. Anticancer Drug Des., 1989, 4(4), 241-263.
[PMID: 2695099]
[26]
McGowan, J.V.; Chung, R.; Maulik, A.; Piotrowska, I.; Walker, J.M.; Yellon, D.M. Anthracycline chemotherapy and cardiotoxicity. Cardiovasc. Drugs Ther., 2017, 31(1), 63-75.
[http://dx.doi.org/10.1007/s10557-016-6711-0] [PMID: 28185035]
[27]
Gardette, M.; Viallard, C.; Paillas, S.; Guerquin-Kern, J.L.; Papon, J.; Moins, N.; Labarre, P.; Desbois, N.; Wong-Wah-Chung, P.; Palle, S.; Wu, T.D.; Pouget, J.P.; Miot-Noirault, E.; Chezal, J.M.; Degoul, F. Evaluation of two 125I-radiolabeled acridine derivatives for Auger-electron radionuclide therapy of melanoma. Invest. New Drugs, 2014, 32(4), 587-597.
[http://dx.doi.org/10.1007/s10637-014-0086-5] [PMID: 24691673]
[28]
Velikyan, I. Prospective of 68Ga-radiopharmaceutical development. Theranostics, 2013, 4(1), 47-80.
[http://dx.doi.org/10.7150/thno.7447] [PMID: 24396515]
[29]
Velikyan, I. 68Ga-based radiopharmaceuticals: production and application relationship. Molecules, 2015, 20(7), 12913-12943.
[http://dx.doi.org/10.3390/molecules200712913] [PMID: 26193247]
[30]
Kilian, K. 68Ga-DOTA and analogs: Current status and future perspectives. Rep. Pract. Oncol. Radiother., 2014, 19(Suppl.), S13-S21.
[http://dx.doi.org/10.1016/j.rpor.2014.04.016] [PMID: 28443194]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy