Alisertib'in İyot-123 ile Radyoişaretlenme Potansiyelinin Araştırılması: Aurora A Kinaz İnhibitörünün Görüntülenme Potansiyelinin Değerlendirilmesi
Abstract
Alisertib (ALS), Aurora kinaz inhibitörleri arasında yer alarak, kanser tedavisinde büyük potansiyel taşımaktdır. Aurora kinazın aşırı ekspresyonu, kromozomal instabilite ve hücre transformasyonuna yol açabilir ve bu, tümör oluşumunda önemli bir rol oynamaktadır. Araştırmalar, özellikle prostat kanseri, kolorektal kanser ve T hücreli lenfomalar gibi çeşitli kanser türlerinde Aurora Kinaz A (AURK-A) ekspresyonunun arttığını göstermektedir. AURK-A ekspresyonunun görüntülenmesi üzerine literatürde kapsamlı çalışmalar bulunmaktadır. Bu araştırma, AURK-A ekspresyonunun İyot-123 [123I] kullanılarak görüntülenmesine yönelik bir ön çalışmadır. Çalışma kapsamında, Alisertib (ALS) bileşiği İyot-123 [123I] (yarı ömrü: 13,2 saat, γ: 159 keV) ile iodojen yöntemi kullanılarak radyoişaretlenmiştir. Elde edilen [123I]I-ALS kompleksinin kalite kontrol süreçleri, İnce Tabaka Radyo Kromatografı (TLRC) tekniği kullanılarak gerçekleştirilmiştir. Ayrıca, inaktif iyot formu olan KI ile yapılan işaretleme sonrası, KI-ALS kompleksinin moleküler yapısı Yüksek Performans Sıvı Kromatografi (HPLC) ve Proton Nükleer Manyetik Rezonans (1H-NMR) teknikleriyle analiz edilmiştir. Yapılan radyokimyasal verim analizleri, [123I]I-ALS'nin %95,1 ± 0,98 (n=3) oranında başarılı bir şekilde radyoişaretlendiğini ve 24 saat sonrasında bile stabilitesinin %90 üzerinde kaldığını belirtmektedir. HPLC sonuçları, KI-ALS kompleksinin ALS bileşiğinden farklı bir alıkonma zamanına (Rt: 2,21 dk.) sahip olduğunu ortaya koymaktadır. NMR verileri ise, [123I]I atomunun ALS molekülündeki aromatik benzen halkasına orto veya para pozisyonunda bağlandığını işaret etmektedir. Bu bağlantının doğruluğunun belirlenmesi için 13C-NMR, LC/MS-QToF ve X-ışını kristalografisi tekniklerinin kullanılması önerilmektedir. Sonuç olarak, bu ön çalışma, AURK-A ekspresyonunun detaylı görüntülenmesi hakkında temel bir bilgi sunmakla birlikte, konunun derinlemesine anlaşılması için daha kapsamlı in vitro ve in vivo preklinik çalışmalarla desteklenmesi gerektiği düşünülmektedir.
Thanks
Makalenin gözden geçirilmesine katkı veren Prof. Dr. Uğur AVCIBAŞI'na teşekkür ederiz.
References
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- Niu, H., Manfredi, M., Ecsedy, J. A. Scientific rationale supporting the clinical development strategy for the investigational Aurora A kinase inhibitor alisertib in cancer. In Frontiers in Oncology, 2015. Vol. 5, Issue Aug https://doi.org/10.3389/fonc.2015.00189
- Schneider, M. A., Christopoulos, P., Muley, T. AURKA, DLGAP5, TPX2, KIF11 and CKAP5: Five specific mitosis-associated genes correlate with poor prognosis for non-small cell lung cancer patients. International Journal of Oncology, 2017 50(2), 365–372. https://doi.org/10.3892/ijo.2017.3834
- Tagal, V., Wei, S., Zhang, W SMARCA4-inactivating mutations increase sensitivity to Aurora kinase A inhibitor VX-680 in non-small cell lung cancers. Nature Communications, 2017 https://doi.org/10.1038/ncomms14098
Investigation of Alisertib's Radiolabeling Potential with Iodine-123: Evaluating the Imaging Capability of the Aurora A Kinase Inhibitor
Abstract
Alisertib (ALS), as an Aurora kinase inhibitor, exhibits significant potential in cancer treatment. The overexpression of Aurora kinase, which can lead to chromosomal instability and cell transformation, plays a vital role in tumor development. Studies have shown an increase in Aurora Kinase A (AURK-A) expression in various cancers, including prostate cancer, colorectal cancer, and T-cell lymphomas. Extensive research exists on imaging methods for AURK-A expression. This study is a preliminary investigation into imaging AURK-A expression using Iodine-123 [123I]. In this research, the Alisertib was radiolabeled with Iodine-123 [123I] (half-life: 13.2 hours, γ: 159 keV) using the iodogen method. The quality control processes [123I]I-ALS carried out using Thin Layer Radio Chromatography (TLRC). Additionally, after labeling with the inactive iodine form, KI, the molecular structure of the KI-ALS was analyzed using High-Performance Liquid Chromatography (HPLC) and Proton Nuclear Magnetic Resonance (1H-NMR). Radiochemical yield analyses indicated that [123I]I-ALS was successfully radiolabeled with a 95.1 ± 0.98% (n=3) efficiency and maintained over 90% stability after 24 hours. HPLC results revealed that the KI-ALS complex had a different retention time (Rt: 2.21 min) compared to the ALS compound. NMR data suggested that the [123I]I atom binds to the aromatic benzene ring of the ALS molecule in either the ortho or para position. To confirm this binding, the use of 13C-NMR, LC/MS-QToF, and X-ray crystallography techniques is recommended. In conclusion, this preliminary study provides fundamental insights into detailed imaging of AURK-A expression, yet emphasizes the need for more comprehensive in vitro and in vivo preclinical studies.
References
- Beltran, H., Rickman, D. S., Park, K., et. al. Molecular characterization of neuroendocrine prostate cancer and identification of new drug targets. Cancer Discovery, (2011). 1(6), 487–495. https://doi.org/10.1158/2159-8290.CD-11-0130
- Borisa, A. C., & Bhatt, H. G. et al, A comprehensive review on Aurora kinase: Small molecule inhibitors and clinical trial studies. European Journal of Medicinal Chemistry, (2017) 140, 1–19. https://doi.org/10.1016/j.ejmech.2017.08.045
- D’Assoro, A. B., Haddad, T., Galanis, et al, E. Aurora-A kinase as a promising therapeutic target in cancer. Frontiers in Oncology, (2016). 5(JAN). https://doi.org/10.3389/fonc.2015.00295
- Ding, Y. H., Zhou, Z. W., Ha, C. F., et al, Alisertib, an Aurora kinase A inhibitor, induces apoptosis and autophagy but inhibits epithelial to mesenchymal transition in human epithelial ovarian cancer cells. Drug Design, Development and Therapy, (2015) 9, 425–464. https://doi.org/10.2147/DDDT.S74062
- Ferris, T., Carroll, L., Jenner, S., Aboagye, E. O. et al, Use of radioiodine in nuclear medicine—A brief overview. In Journal of Labelled Compounds and Radiopharmaceuticals, 2021, pp. 92–108). https://doi.org/10.1002/jlcr.3891
- Friedberg, J. W., Mahadevan, D., Cebula, et al, E. Phase ii study of alisertib, a selective aurora a kinase inhibitor, in relapsed and refractory aggressive B- And T-cell non-Hodgkin lymphomas. Journal of Clinical Oncology, (2014) 32(1), 44–50. https://doi.org/10.1200/JCO.2012.46.8793
- Gerson, J. N., Handorf, E., Villa, D et al, Survival Outcomes of Younger Patients With Mantle Cell Lymphoma Treated in the Rituximab Era. J Clin Oncol, 2019, 37, 471–480. https://doi.org/10.1200/JCO.18.00690
- Goos, J. A., Verbeek, J., Geldof, A. A. et al. Molecular imaging of aurora kinase A (AURKA) expression: Synthesis and preclinical evaluation of radiolabeled alisertib (MLN8237). Nuclear Medicine and Biology, (201643(1), 63–72. https://doi.org/10.1016/j.nucmedbio.2015.08.007
- Locatelli, E., Naddaka, M., Uboldi et al. Targeted delivery of silver nanoparticles and alisertib: In vitro and in vivo synergistic effect against glioblastoma. Nanomedicine, 2014, 9(6), 839–849. https://doi.org/10.2217/nnm.14.1
- Malumbres, M., Pérez De Castro Aurora kinase A inhibitors: Promising agents in antitumoral therapy. In Expert Opinion on Therapeutic Targets 2014, pp. 1377–1393 https://doi.org/10.1517/14728222.2014.956085
- Mignogna, C., Staropoli, N., Botta, C., Aurora Kinase A expression predicts platinum-resistance and adverse outcome in high-grade serous ovarian carcinoma patients—Journal of Ovarian Research, 2016, 9(1). https://doi.org/10.1186/s13048-016-0238-7
- Niu, H., Manfredi, M., Ecsedy, J. A. Scientific rationale supporting the clinical development strategy for the investigational Aurora A kinase inhibitor alisertib in cancer. In Frontiers in Oncology, 2015. Vol. 5, Issue Aug https://doi.org/10.3389/fonc.2015.00189
- Schneider, M. A., Christopoulos, P., Muley, T. AURKA, DLGAP5, TPX2, KIF11 and CKAP5: Five specific mitosis-associated genes correlate with poor prognosis for non-small cell lung cancer patients. International Journal of Oncology, 2017 50(2), 365–372. https://doi.org/10.3892/ijo.2017.3834
- Tagal, V., Wei, S., Zhang, W SMARCA4-inactivating mutations increase sensitivity to Aurora kinase A inhibitor VX-680 in non-small cell lung cancers. Nature Communications, 2017 https://doi.org/10.1038/ncomms14098
Details
| Primary Language | Turkish |
|---|---|
| Subjects | Physical Chemistry (Other) |
| Journal Section | Articles |
| Authors | |
| Early Pub Date | September 10, 2024 |
| Publication Date | October 1, 2024 |
| Submission Date | October 18, 2023 |
| Acceptance Date | July 29, 2024 |
| Published in Issue | Year 2024 |
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