Ön İlaçların Tasarımı ve Kanser Tedavisindeki Fonksiyonları

Yıl 2024, Cilt: 4 Sayı: 1, 35 - 43, 22.05.2024

Esra Karagül Ozge Soylu

https://doi.org/10.5281/zenodo.11219685

Öz

Ön ilaçlar, ana ilaçlardan yararlanma miktarını arttırmak için tasarlanan ve kimyasal modifikasyonlarla elde edilen inaktif ilaç formlarıdır. Bu ilaçlar, farmakolojik olarak inaktif olup in vivo ortamda ya da insan vücudunda aktive olabilmektedir. İlaçların farmasötik, farmakodinamik ve/veya farmakokinetik özelliklerini iyileştirmek veya hedeflemeyi sağlamak amacıyla ana ilaç moleküllerinden ön ilaçlar türevlendirilmektedir. Ön ilaçların biyoaktivasyonu, türevlendirmeyi sağlayan fonksiyonel grupların enzimatik veya non-enzimatik reaksiyona uğraması ile mümkün olmaktadır. Biyoaktivasyonu sağlayan araçların hedef dokuya spesifik olmasıyla istenen dokuya hedeflendirme de sağlanabilmektedir. Antikanser ilaçların sağlıklı hücrelere sitotoksik etki göstermesi sebebiyle ön ilaç stratejisi, kanser tedavisinde de ilgi görmektedir. Tümöre özgü özellikleri hedef alan ön ilaçlar sayesinde selektif bir tedavi sağlanabilmekte ve sağlıklı hücrelerin zarar görmesi azaltılmaktadır. Bu çalışmada, ön ilaçların kavramsal çerçevesi çizilerek önemi vurgulandı, amaçları, hazırlama yöntemleri ve hedefleme teknikleri ön ilaç örnekleri ile incelendi. Ayrıca ön ilaçların kanser tedavisindeki yeri ve kullanımı güncel araştırmalar ışığında özetlendi.

Anahtar Kelimeler

Ön ilaç, biyoaktivasyon, hedeflendirme, kanser, selektivite.

Design of Prodrugs and Their Functions in Cancer Treatment

Öz

Prodrugs are inactive drug forms that are generated chemically modifications with the intention of increasing the availability of parent drugs. These drugs can be activated in vivo or inside the human body, despite being pharmacologically inactive. To ensure targeting or enhance the pharmaceutical, pharmacodynamic, and/or pharmacokinetic qualities of medications, prodrugs are derived from parent drug molecules. Enzymatic or non-enzymatic reactions of functional groups that provide derivatization are the means by which prodrugs are bioactivated. Targeting to the intended tissue can also be accomplished because the instruments used to produce bioactivation are specific to the target tissue. The prodrug approach is likewise relevant to the treatment of cancer because anticancer drugs have cytotoxic effects on healthy cells. Targeted prodrugs, which focus on tumor-specific features, allow for selective treatment and reduce damage to healthy cells. The theoretical framework of prodrugs was outlined in this paper, emphasizing on their significance, objectives, preparation methods, and targeting techniques, along with examples of prodrugs, along with examples of prodrugs. Additionally, the current research provided a summary of the usage and breadth of prodrugs in cancer treatment.

Anahtar Kelimeler

Prodrug, design, targeting, cancer, selectivity

Kaynakça

• [1] Di L, Kerns EH. Drug-Like Properties: Concepts, Structure Design and Methods from ADME to Toxicity Optimization. Academic Press, 2016:1-3.
• [2] Choudhary D, Goykar H, Kalyane D, et al. Prodrug design for improving the biopharmaceutical properties of therapeutic drugs. The Future of Pharmaceutical Product Development and Research, Academic Press. London.2020:179-226.
• [3] Albert A. Selective Toxicity: The physico-chemical basis of therapy. Springer. Berlin. 1985.
• [4] Harper NJ. Drug Latentiation. J Med Chem. 1959;1(5):467-500.
• [5] Abelian A, Michael D, Wallach J, et al. Pharmaceutical Chemistry. Remington The Science and Practice of Pharmacy, Academic Press. Philadelphia. 2020:105-128.
• [6] Rautio J, Laine K, Gynther M, et al. Prodrug approaches for CNS delivery. The AAPS Journal. 2008;10(1):92-102.
• [7] Ayanoğlu G. İlaç Taşınmasını Kolaylaştırma Yönünden Ön–ilaç (pro – drug) şekli. J Pharm Sci. 1980;5(1):7-10.
• [8] Alagöz Z, Adejare A. Prodrugs. Pharm Chem. 2021;9:169-186.
• [9] Huttunen KM, Raunio H, Rautio J. Prodrugs-from serendipity to rational design. Pharmacol Rev. 2011;63(3):750-771.
• [10] Karaman R. Prodrugs-Current and Future Drug Development Strategy. IJMPCR. 2014;1(2):58-63.
• [11] Walther R, Rautio J, Zelikin AN. Prodrugs in medicinal chemistry and enzyme prodrug therapies. Adv Drug Deliv Rev. 2017;118:65-77.
• [12] Gandhi P, Chabukswar A, Jagdale S. Carriers for Prodrug Synthesis: A Review. Indian J Pharm Sci. 2019;81(3):406-414.
• [13] Markovic M, Ben-Shabat S, Dahan A. Prodrugs for Improved Drug Delivery: Lessons Learned from Recently Developed and Marketed Products. Pharm. 2020;12(11):1031.
• [14] Rita B, Akhilesh T. Prodrug: Design and Its Applications. J Pharm Nanotechnol. 2015;3(2):103-106.
• [15] Shin JM, Cho YM, Sachs G. Chemistry of Covalent Inhibition of the Gastric (H+, K+)-ATPase by Proton Pump Inhibitors. J Am Chem Soc. 2004;126(25):7800-7811.
• [16] Stella V, Borchardt R, Hageman M, et al. Prodrugs: Challenges and Rewards. In V. Stella, R. Borchardt, M. Hageman, R. Oliyai, H. Maag, J. Tilley, Biotechnology, AAPS Press and Springer, New York.2007;1:3-36,.
• [17] Stella V, Charman W, Naringrekar V. Prodrugs Do They Have Advantages in Clinical Practice. Drugs. 1985;29: 455-473.
• [18] Hajnal K, Gabriel H, Aura R, et al. Prodrug Strategy in Drug Development. Acta Marisiensis Seria Med. 2016;62(3):356-362.
• [19] Choi-Sledeski Y, Wermuth C. Designing Prodrugs and Bioprecursors. The Practice of Medicinal Chemistry, Academic Press, 2015:657-692.
• [20] Abet V, Filace F, Recio J, et al. Prodrug approach: An overview of recent cases. Eur J Med Chem. 2017;127:810-827.
• [21] Chauhan A, Khan T. Prodrugs - Current Development and Applications in Ocular Drug Delivery. J Drug Deliv Sci Technol. 2021;66(9):102836.
• [22] Ita K. Prodrugs. Transdermal Drug Delivery Concepts and Applications. 2020;7:123-141,
• [23] N'Da DD. Prodrug strategies for enhancing the percutaneous absorption of drug. Molecules. 2014;19(12):20780-20807.
• [24] Wu K. A New Classification of Prodrugs: Regulatory Perspectives. Pharm. 2009;2(3):77-81.
• [25] Yokuş B, Ülker DÜ. Kanser biyokimyası. Dicle Üniv Vet Fak Derg. 2012;1(2):7-18.
• [26] Oylar Ö, Tekin İ. Kanserin teşhis ve tedavisinde nanoteknolojinin önemi. UUJFE. 2011;16(1):147-154.
• [27] Roy P, Saikia B. Cancer and cure: A critical analysis. Indian J Cancer. 2016;53(3):441-442.
• [28] Hanahan D, Weinberg R. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646-674.
• [29] Hanahan D. Hallmarks of Cancer: New Dimensions. Cancer Discov. 2022;12(1):31-46.
• [30] Sharma SK, Bagshawe KD. Antibody Directed Enzyme Prodrug Therapy (ADEPT): Trials and tribulations. Adv Drug Deliv Rev. 2017;118:2-7.
• [31] Baykara O. Kanser Tedavisinde Güncel Yaklaşımlar. BAUN Sağ Bil Derg. 2016;5(3):154-165.
• [32] Singh Y, Palombo M, Sinko P. Recent Trends in Targeted Anticancer Prodrug and Conjugate Design. Curr Med Chem. 2008;15(18):1802-1826.
• [33] Denny W. Prodrug strategies in cancer therapy. Eur J Med Chem. 2001;36(7-8):577-595.
• [34] Knox R, Freiedlos F, Marchbank T, et al. Bioactivation of CB 1954: reaction of the active 4-hydroxylamino derivative with thioesters to form the ultimate DNA-DNA interstrand crosslinking species. Biochem Pharmacol. 1991;42(9):1691-1697.
• [35] Rais R, Lemberg KM, Tenora L, et al. Discovery of DRP-104, a tumor-targeted metabolic inhibitor prodrug. Sci Adv. 2022;18;8(46):eabq5925.
• [36] Wilson W, Hay M. Targeting hypoxia in cancer therapy. Nat Rev Cancer. 2011;11(6):393-410.
• [37] Guise C, Mowday A, Ashoorzadeh A, et al. Bioreductive prodrugs as cancer therapeutics: targeting tumor hypoxia. Chin J Cancer. 2014;33(2):80-86.
• [38] Graham K, Unger E. Overcoming tumor hypoxia as a barrier to radiotherapy, chemotherapy and immunotherapy in cancer treatment. Int J Med. 2018;13:6049-6058.
• [39] Denny W. The Design of Selectively-Activated Prodrugs for Cancer Chemotherapy. Curr Pharm Des. 1996;2(3):281-294.
• [40] Zhang X, Li X, You Q, et al. Prodrug strategy for cancer cell-specific targeting: A recent overview. Eur J Med Chem. 2017;139:542-563.
• [41] Zheng S, Li G, Shi J, et al. Emerging platinum(IV) prodrug nanotherapeutics: A new epoch for platinum-based cancer therapy. J Control Release. 2023;361:819-846.
• [42] McAdam AD, Batchelor LK, Romano-deGea J, et al. Thermoresponsive carboplatin-releasing prodrugs. J Inorg Biochem. 2024;254:112505.
• [43] Prange CJ, Sayed NYB, Feng B, et al. A redox-responsive prodrug for tumor-targeted glutamine restriction. J Control Release. 2024:368;251-264.
• [44] Sun J, Yao H, Ren X, et al. Radiation-Activated Resiquimod Prodrug Nanomaterials for Enhancing Immune Checkpoint Inhibitor Therapy. Nano Lett. 2024; 24(9):2921-2930.
• [45] Farrer NJ, Higgins GS, Kunkler IH. Radiation-induced prodrug activation: extending combined modality therapy for some solid tumours. Br J Cancer. 2022;126(9):1241-1243.