ALZHEIMER TANISI İÇİN LÖKO METİLTİYONİNYUM BİS-İÇEREN NANOPARTİKÜLLERİN KARAKTERİZASYONU

Öz

Amaç: Bu çalışmada Alzheimer hastalığının tanısında kullanılan radyofarmasötiklerin farmasötik kısmı için yeni formülasyonlar geliştirmek amaçlanmaktadır. Bu amaçla kitosan yapılı nanotaşıyıcı sistemler geliştirilmiştir. Radyofarmasötiğin farmasötik kısmında aktif madde olarak löko metiltiyoninyum bis (hidro metan sülfonat) (LMT) kullanılacaktır. Gereç ve Yöntem: Nanotaşıyıcı formülasyonlar iyonik çapraz bağlama tekniği kullanılarak hazırlandı. Yağ fazında asetik asit ve kitosan kullanıldı. Su fazında distile su ve glutaraldehit kullanıldı. Span 80 yüzey aktif madde olarak kullanıldı. Hazırlanan formülasyonların karakterizasyon çalışmaları Malvern Zeta Sizer ölçümleri kullanılarak gerçekleştirilmiştir. LMT aktif bileşeninin sitotoksisite çalışmaları MTT kiti kullanılarak gerçekleştirilmiştir. Sonuç ve Tartışma: Karakterizasyon çalışmaları, partikül boyutu 100-200 nm ve zeta potansiyeli -20mV'den düşük ve +20mV'den büyük olan formülasyonların seçilmesiyle sonuçlandı. SH-SY5Y hücreleri üzerinde yapılan çalışmada sitotoksik etkisinin olmadığı gözlemlendi. Hazırlanan formülasyonların karakterizasyon çalışmaları Alzheimer hastalığının teşhisinde kullanım açısından umut verici bulunmuş olup, belirlenen formülasyonlarla çalışmalara devam edilecektir.

Anahtar Kelimeler

• Alzheimer hastalığı
• löko metiltiyoninyum bis
• nanopartikül
• sitotoksisite

CHARACTERIZATION OF LEUCO METHYLTHIONINIUM BIS-CONTAINING NANOPARTICLES FOR ALZHEIMER’S DIAGNOSIS

Öz

Objective: This research aims to develop new formulations for the pharmaceutical component of radiopharmaceuticals used to diagnose Alzheimer's disease. For this purpose, chitosan nanocarrier systems have been developed. The active ingredient of the pharmaceutical component of the radiopharmaceutical will be leuco methylthioninium bis (hydro methane sulfonate) (LMT). Material and Method: Nanocarrier formulations were prepared using the ionic cross-linking technique. Acetic acid and chitosan were used in the oil phase. Distilled water and glutaraldehyde were used in the water phase. Span 80 was used as a surfactant. Characterization studies of the prepared formulations were carried out using Malvern Zeta Sizer measurements. The MTT kit conducted cytotoxicity tests on the LMT active component. Result and Discussion: The characterization studies selected formulations with a 100-200 nm particle size and a zeta potential of less than -20mV and greater than +20mV. In the study conducted on SH-SY5Y cells, it was observed that it had no cytotoxic effect. The characterization studies of the prepared formulations found them promising for use in diagnosing Alzheimer's disease, and studies with the determined formulations will continue.

Anahtar Kelimeler

• Alzheimer's disease
• cytotoxicity
• leuco methylthioninium bis
• nanoparticle

Kaynakça

1. 1. Anand, P., Singh, B. (2013). A review on cholinesterase inhibitors for Alzheimer’s disease. Archives of Pharmacal Research, 36(4), 375-399. [CrossRef]
2. 2. Armstrong, R.A. (2019). Risk factors for Alzheimer’s disease. Folia Neuropathologica, 57(2), 87-105. [CrossRef]
3. 3. Breijyeh, Z., Karaman, R. (2020). Comprehensive review on Alzheimer’s disease: Causes and treatment. Molecules, 25(24), 1-2. [CrossRef]
4. 4. Gaudette, N.F., Lodge, J.W. (2005). Determination of methylene blue and leucomethylene blue in male and female Fischer 344 rat urine and B6C3F1 mouse urine. Journal of Analytical Toxicology, 29(1), 28-33. [CrossRef]
5. 5. Wainwright, M., Amaral, L. (2005). Review: The phenothiazinium chromophore and the evolution of antimalarial drugs. Tropical Medicine and International Health, 10(6), 501-511. [CrossRef]
6. 6. Panza, F., Solfrizzi, V., Seripa, D., et al. (2016). Tau-centric targets and drugs in clinical development for the treatment of Alzheimer’s disease. BioMed Research International. [CrossRef]
7. 7. Manek, E., Darvas, F., Petroianu, G.A. (2020). Use of biodegradable, chitosan-based nanoparticles in the treatment of alzheimer’s disease. Molecules, 25(20). [CrossRef]
8. 8. Wong, K.H., Riaz, M.K., Xie, Y., et al. (2019). Review of current strategies for delivering Alzheimer’s disease drugs across the blood-brain barrier. International Journal of Molecular Sciences, 20(2), 2-5. [CrossRef]

9. 9. Adepu, S., Ramakrishna, S. (2021). Controlled drug delivery systems: Current status and future directions. Molecules, 26(19). [CrossRef]
10. 10. Torchilin, V. (2008). Multifunctional Pharmaceutical Nanocarriers: Development of the Concept. Ed: Torchilin, V. Fundamental Biomedical Technologies Multifunctional Pharmaceutical Nanocarriers, Springer New York, New York, 1-32.
11. 11. Ali, A., Ahmed, S. (2018). A review on chitosan and its nanocomposites in drug delivery. International Journal of Biological Macromolecules, 109, 273-286. [CrossRef]
12. 12. Sharifi-Rad, J., Quispe, C., Butnariu, M., et al. (2021). Chitosan nanoparticles as a promising tool in nanomedicine with particular emphasis on oncological treatment. Cancer Cell International, 21(1), 318. [CrossRef]
13. 13. Prabaharan, M. (2015). Chitosan-based nanoparticles for tumor-targeted drug delivery. International Journal of Biological Macromolecules, 72, 1313-1322. [CrossRef]
14. 14. Ravi Kumar, M.N.V. (2000). A review of chitin and chitosan applications. Reactive and Functional Polymers, 46(1), 1-27. [CrossRef]
15. 15. Hasanifard, M., Ebrahimi-Hosseinzadeh, B., Hatamian-Zarmi, A., et al. (2018). Development of thiolated chitosan nanoparticles based mucoadhesive vaginal drug delivery systems. Polymer Science, Series A, 59(6), 858-865. [CrossRef]
16. 16. Mohammed, M.A., Syeda, J.T.M., Wasan, K.M., Wasan, E.K. (2017). An overview of chitosan nanoparticles and its application in non-parenteral drug delivery. Pharmaceutics, 9(4). [CrossRef]
17. 17. Yanat, M., Schroën, K. (2021). Preparation methods and applications of chitosan nanoparticles; with an outlook toward reinforcement of biodegradable packaging. Reactive and Functional Polymers, 161. [CrossRef]
18. 18. Medellín-Castillo, N.A., Isaacs-Páez, E.D., Rodríguez-Méndez, I., et al. (2021). Formaldehyde and tripolyphosphate crosslinked chitosan hydrogels: Synthesis, characterization and modeling. International Journal of Biological Macromolecules 183, 2293-2304. [CrossRef]
19. 19. Silindir Günay, M. (2020). The formulation of methylene blue encapsulated, tc-99m labeled multifunctional liposomes for sentinel lymph node imaging and therapy. Turkish Journal of Pharmaceutical Sciences, 17(4), 381-387. [CrossRef]
20. 20. Khadieva, A., Mostovaya, O., Padnya, P., et al. (2021). Arylamine analogs of methylene blue: Substituent effect on aggregation behavior and dna binding. International Journal of Molecular Sciences, 22(11), 5847. [CrossRef]
21. 21. Elhabak, M., Ibrahim, S., Abouelatta, S.M. (2021). Topical delivery of l-ascorbic acid spanlastics for stability enhancement and treatment of UVB induced damaged skin. Drug Delivery, 445-453. [CrossRef]
22. 22. Khan, M.M., Madni, A., Torchilin, V., et al. (2019). Lipid-chitosan hybrid nanoparticles for controlled delivery of cisplatin. Drug Delivery, 26(1), 765-772. [CrossRef]
23. 23. Wu, P.T., Lin, C.L., Lin, C.W., et al. (2019). Methylene-blue-encapsulated liposomes as photodynamic therapy nano agents for breast cancer cells. Nanomaterials, 9(1), 14. [CrossRef]
24. 24. Haouzi, P., McCann, M., Wang, J.F., et al. (2020). Antidotal effects of methylene blue against cyanide neurological toxicity: In vivo and in vitro studies. Annals of the New York Academy of Sciences, 1479(1), 108-121. [CrossRef]
25. 25. Wilcock, G.K., Gauthier, S., Frisoni, G.B., et al. (2018). Potential of low dose leuco-methylthioninium bis(hydromethanesulphonate) (LMTM) monotherapy for treatment of mild alzheimer's disease: Cohort analysis as modified primary outcome in a phase III clinical trial. Journal of Alzheimer’s disease, 61(1), 435-457. [CrossRef]
26. 26. Thangwaritorn, S., Lee, C., Metchikoff, E., et al. (2024). A review of recent advances in the management of Alzheimer's disease. Cureus, 16(4), e58416. [CrossRef]
27. 27. Seo, D.H., Huh, Y.H., Cheong, H.K., et al. (2024). Mechanism of methylene blue inducing the disulfide bond formation of tubulin-associated unit proteins. JACS Au, 4(7), 2451-2455. [CrossRef]