Volume 22, Issue 3 (Iranian South Medical Journal 2019)
Iran South Med J 2019, 22(3): 160-173 |
Back to browse issues page
Download citation:
BibTeX | RIS | EndNote | Medlars | ProCite | Reference Manager | RefWorks
Send citation to:
BibTeX | RIS | EndNote | Medlars | ProCite | Reference Manager | RefWorks
Send citation to:
Houshdar Tehrnai M H, Mohammadpoor M, Shahhosseini S. Design, Synthesis and Labeling of Tripeptide Derivatives with 99mTc as Hypoxia Imaging Agents. Iran South Med J 2019; 22 (3) :160-173
URL: http://ismj.bpums.ac.ir/article-1-1095-en.html
URL: http://ismj.bpums.ac.ir/article-1-1095-en.html
1- Phrmaceutical Chemistry& Neuclear Medicine Dept, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran , m_houshdar@sbmu.ac.ir
2- Pharmaceutical Sciences Branch, Islamic Azad University, Tehran, Iran
3- Phrmaceutical Chemistry& Neuclear Medicine Dept, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran
2- Pharmaceutical Sciences Branch, Islamic Azad University, Tehran, Iran
3- Phrmaceutical Chemistry& Neuclear Medicine Dept, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran
Abstract: (3025 Views)
Background: Many diseases, including cancer, ischemia and tumors show degrees of tissue hypoxia.Therefore, it is useful to detect tissue hypoxia with compounds that can penetrate and remain in hypoxic cells in order to diagnose cancer at early stages. Peptides with low molecular weight, susceptible to redox environment, with easier penetration into tissues and low antigenic characteristics are good candidates,as compared to antibodies and proteins. Therefore, radiolabeling small lipophilic peptides containing a nitro group with 99mTc to enter and remain in the hypoxic cell for imaging hypoxic tissue is a good strategy for earlier detection of tumors, which leads to more effective and satisfactory treatment.
Materials and Methods: In this study, some tripeptides were synthesized with added para nitro benzoic acid (PNBA) group at their N-terminal using solid phase peptide synthesis (SPPS) method with Fmocstrategy using Wang resin. The peptides were labeled with 99mTc and their characterizations were determined using chromatographic techniques and partition coefficient experiments. A hypoxia Jar system was used to examine cellular uptake of the labeled peptides exposed to MCF-7 cells in normal and hypoxic conditions for 30 to 120 min.
Results: Synthesis of the peptides resulted in good yields (70% to 78%). The synthesized peptides andradiopeptides were stable in normal saline and human plasma for at least 4 h and 6 h, respectively.Radiochemical purity (RCP) of the synthesized labeled peptides was 94% with lipophilicity (Log P)
-0.006. Furthermore, labeled peptides exposed to MCF-7 cells could remain in hypoxic cells longer than those in normal cells.
Conclusion: Considering the results obtained in this study, the peptide derivatives labeled with 99mTc,appear to be appropriate agents for the detection and imaging of hypoxic tissues.
Materials and Methods: In this study, some tripeptides were synthesized with added para nitro benzoic acid (PNBA) group at their N-terminal using solid phase peptide synthesis (SPPS) method with Fmocstrategy using Wang resin. The peptides were labeled with 99mTc and their characterizations were determined using chromatographic techniques and partition coefficient experiments. A hypoxia Jar system was used to examine cellular uptake of the labeled peptides exposed to MCF-7 cells in normal and hypoxic conditions for 30 to 120 min.
Results: Synthesis of the peptides resulted in good yields (70% to 78%). The synthesized peptides andradiopeptides were stable in normal saline and human plasma for at least 4 h and 6 h, respectively.Radiochemical purity (RCP) of the synthesized labeled peptides was 94% with lipophilicity (Log P)
-0.006. Furthermore, labeled peptides exposed to MCF-7 cells could remain in hypoxic cells longer than those in normal cells.
Conclusion: Considering the results obtained in this study, the peptide derivatives labeled with 99mTc,appear to be appropriate agents for the detection and imaging of hypoxic tissues.
Type of Study: Original |
Subject:
Physiology
Received: 2019/01/1 | Accepted: 2019/03/13 | Published: 2019/07/1
Received: 2019/01/1 | Accepted: 2019/03/13 | Published: 2019/07/1
References
1. Mason RP, Zhao D, Pacheco-Torres J, et al. Multimodality Imaging of Hypoxia in Preclinical Settings. Q J Nucl Med Mol Imaging 2010; 54(3): 259-80. [PubMed]
2. Dhani N, Fyles A, Hedley D, et al. The Clinical Significance of Hypoxia in Human Cancers. Semin Nucl Med 2015; 45(2): 110-21. [Article]
3. Mees G, Dierckx R, Vangestel C, et al. Molecular Imaging of Hypoxia with Radiolabelled Agents. Eur J Nucl Med Mol Imaging 2009; 36(10): 1674-86. [Article]
4. Krohn KA, Link JM, Mason RP. Molecular Imaging of Hypoxia. J Nucl Med 2008; 49: 129S-48S. [PubMed]
5. Span PN, Bussink J. Biology of Hypoxia. Semin Nucl Med 2015; 45(2): 101-9. [Article]
6. Langen KJ, Eschmann SM. Correlative Imaging of Hypoxia and Angiogenesis. J Nucl Med 2008; 49(4): 515-6. [Article]
7. Linder KE, Chan Y-W, Cyr JE, et al. TcO (PnA. O-1-(2-nitroimidazole))[BMS-181321], A New Technetium-containing Nitroimidazole Complex for Imaging Hypoxia: Synthesis, Characterization, and Xanthine Oxidase-catalyzed Reduction .J Med Chem 1994; 37(1): 9-17. [PubMed]
8. Nunn A, Linder K, Strauss HW. Nitroimidazoles and Imaging Hypoxia. Eur J Nucl Med 1995; 22(3): 265-80. [Article]
9. Le QT, Courter D. Clinical Biomarkers for Hypoxia Targeting. Cancer Metastasis Rev 2008; 27(3): 351-62. [Article]
10. Varia MA, Calkins-Adams DP, Rinker LH, et al. Pimonidazole: A Novel Hypoxia Marker for Complementary Study of Tumor Hypoxia and Cell Proliferation in Cervical Carcinoma. Gynecol Oncol 1998; 71(2): 270-7. [Article]
11. Melo T, Tunggal JK, Ballinger JR, et al. Flux Through Multicellular Layers of A Technetium-99m-Nitroimidazole for Imaging Hypoxia. Cancer Biother Radiopharm 2002; 17(5): 515-26. [PubMed]
12. Rezaeianpour S, Mosayebnia M, Bozorgi AH, et al. Design, Synthesis and Radiolabeling of Peptide GPRPILE with 18FDG as Fibrin Imaging Agent for Thrombosis Detection. Iran South Med J 2018; 21(3): 228-41. [Article]
13. Liu S, Edwards DS. 99mTc-labeled Small Peptides As Diagnostic Radiopharmaceuticals. Chem Rev 1999; 99(9): 2235-68 [Article]
14. Klimentzou P, Beck A, Varvarigou A, et al. Solid‐phase Synthesis of a Peptide Derivative of Thymosin alpha1 and Initial Studies on its 99mTc‐Radiolabelling. Chem Biol Drug Des 2007; 70: 40-6 [Article]
15. Couture F, Levesque C, Dumulon-Perreault V, et al. PACE4-based Molecular Targeting of Prostate Cancer Using An Engineered 64 Cu-radiolabeled Peptide Inhibitor. Neoplasia 2014; 16(8): 634-43 [Article]
16. Karachaliou CE, Liolios C, Triantis C, et al. Specific in Vitro Binding of Prothymosin alpha on Human Neutrophils. Int J Pharm 2015; 486(1-2):1-12. [Article]
17. Hausner SH, Bauer N, Hu LY, et al. The Effect of Bi-Terminal PEGylation of an Integrin αvβ6–Targeted 18F Peptide on Pharmacokinetics and Tumor Uptake. J Nucl Med 2015; 56(5): 784-90. [Article]
18. Zhang X, Su ZF, Ballinger JR, et al. Targeting Hypoxia in Tumors Using 2-nitroimidazoles with Peptidic Chelators for Technetium-99m: Effect of Lipophilicity. Bioconjug Chem 2000; 11: 401-7. [Article]
19. Rezaeianpour S, Bozorgi AH, Moghimi A, et al. Synthesis and Biological Evaluation of Cyclic [99mTc]-HYNIC-CGPRPPC as a Fibrin-Binding Peptide for Molecular Imaging of Thrombosis and Its Comparison with [99mTc]-HYNIC-GPRPP. Mol Imaging Biol 2017; 19(2):256-64 [Article]
20. Mosayebnia M, Hajiramezanali M, Shahhosseini S, et al. Docking, synthesis, in-vitro evaluation, and optimization of reaction conditions for direct radiolabeling of CGPRPPC with technetium-99m through the GAGG sequence. Nucl Med Commun 2018; 39(11): 976-82. [PubMed]
21. Rasey JS, Koh W-J, Grierson JR, et al. Radiolabeled Fluoromisonidazole As Imaging Agent for Tumor Hypoxia. Int J Radiat Oncol Biol Phys 1989; 17(5): 985-91. [Article]
Send email to the article author
| Rights and Permissions | |
 |
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License. |
