Fototermal Tedavi ve Manyetik Rezonans Performansı Üzerine Metal İyonu ile Şelatlanmış Doğal Melanin Nanopartiküllerinin In Vitro ve In Silico Değerlendirilmesi

Öz

Doğal melanin nanoparçacıklarının (MNP) metal iyonu ile şelatlanmış formları, teranostik uygulamalar için güçlü bir potansiyel sergilemektedir. Bununla birlikte gerek dışarıdan uygulanan modifikasyonların, gerekse uygulama sırasında kendiliğinden ortaya çıkan değişimlerin yol açtığı çapraz etkiler (metal iyon şelatlamasının fototermal terapi (PTT) verimliliği üzerindeki etkisi veya PTT kaynaklı sıcaklık değişimlerinin manyetik rezonans görüntü (MRG) kontrastına etkisi gibi) yeterince anlaşılamamıştır. Bu çalışma, söz konusu karşılıklı etkileri hesaplamalı modelleme ve in vitro deneylerle incelemektedir. Bu çalışmada MNP'ler ve metal iyonu ile şelatlanmış MNP'ler sentezlenmiş, PC-3 hücrelerinde karakterize edilmiş ve sitotoksisiteleri değerlendirilmiştir. Düşük sitotoksisite gösteren demir-şelatlanmış MNP'lerin PTT performansı, şelatlanmamış form ile COMSOL simülasyonları ve in vitro modeller kullanılarak karşılaştırılmıştır. Ayrıca PTT öncesi ve sonrasında MRG kontrastı değerlendirilmiştir. Hesaplamalı ve deneysel bulguların her ikisi de Fe3+-şelatlanmış MNP'lerin şelatlanmamış MNP'lere kıyasla daha yüksek PTT performansı sergilediğini ve tedavi sonrasında MRG kontrastında ölçülebilir bir azalma meydana geldiğini göstermiştir. Bu bulgular, Fe3+-şelatlanmış MNP'lerin etkili bir PTT sağlarken aynı zamanda kanser tedavisi sırasında MRG tabanlı dozimetrik izleme olanağı sunan umut verici teranostik ajanlar olduğunu düşündürmektedir.

Anahtar Kelimeler

• doğal melanin nanoparçacıkları
• fototermal terapi
• kanser terapileri
• kontrast ajanları
• manyetik rezonans görüntüleme

In Vitro and In Silico Evaluation of Metal Ion Chelated Natural Melanin Nanoparticles on Photothermal Therapy and Magnetic Resonance Performance

Öz

Metal ion-chelated natural melanin nanoparticles exhibit strong potential for theranostic applications. However, cross-effects resulting from modifications, whether introduced externally or occurring spontaneously during application, such as the influence of metal ion chelation on photothermal therapy (PTT) efficiency and the effect of PTT-induced temperature changes on MRI contrast, remain poorly understood. This study investigates these interrelated effects through computational modelling and in vitro experiments. Melanin nanoparticles (MNPs) and metal ion-chelated MNPs are synthesized, characterized, and evaluated for cytotoxicity in PC-3 cells. The PTT performance of the less cytotoxic iron-chelated MNPs is compared to that of the unchelated form using COMSOL simulations and in vitro models. MRI contrast is also assessed before and after PTT. Both computational and experimental results show that Fe³+-chelated MNPs exhibit enhanced PTT performance compared to unchelated MNPs, along with a measurable decrease in MRI contrast following treatment. These findings suggest that Fe3+-chelated MNPs are promising theranostic agents capable of delivering effective PTT while enabling MRI-based dosimetric monitoring during cancer therapy.

Anahtar Kelimeler

• natural melanin nanoparticles
• phototermal therapy
• cancer therapies
• contrast agents
• magnetic resonance imaging

Kaynakça

1. Bayrak, E., Bayır, E., Baysoy, E., Özcan, A., Ayan, B., Saygılı, E., & Kaleli-Can, G. (2025). Nintedanib loaded iron (III) chelated melanin nanoparticles as an MRI-visible antifibrotic drug delivery system. Colloids and Surfaces B: Biointerfaces, 252, 114652. https://doi.org/10.1016/j.colsurfb.2025.114652
2. Baysoy, E., Ayan, B., Kaleli-Can, G., & Büyüksaraç, B. (2023, November 10-12). Passive device tracking for interventional MRI with ferric ion chelated natural melanin nanoparticles [Paper presentation]. 2023 Medical Technologies Congress (TIPTEKNO), Famagusta, Cyprus. IEEE.
3. Baysoy, E., Kaleli-Can, G., Ayan, B., Özcan, A., Kocatürk, Ö., & Liu, C. (2024). Kiosk 10R-TC-09 – Enhanced balloon catheter visualization with biocompatible melanin nanoparticles in 3T MRI. Journal of Cardiovascular Magnetic Resonance, 26, 100278. https://doi.org/10.1016/j.jocmr.2024.100278
4. Baysoy, E., Kaleli Can, G., Özcan, A., & Liu, C. (2023).Passive device tracking for interventional MRI with ferric ion chelated natural melanin nanoparticles. *ISMRM 2023 - Proceedings of the InternationalSociety for Magnetic Resonance in Medicine, 31*.[Abstract]
5. Caldas, M., Santos, A. C., Veiga, F., Rebelo, R., Reis, R. L., & Correlo, V. M. (2020). Melanin nanoparticles as a promising tool for biomedical applications: A review. Acta Biomaterialia, 105, 142–157. https://doi.org/10.1016/j.actbio.2020.01.044
6. Chen, A., Sun, J., Liu, S., Li, L., Peng, X., Ma, L., & Zhang, R. (2020). The effect of metal ions on endogenous melanin nanoparticles used as magnetic resonance imaging contrast agents. Biomaterials Science, 8(1), 379–390. https://doi.org/10.1039/c9bm01580a
7. Clement, M., Daniel, G., & Trelles, M. (2005). Optimising the design of a broad-band light source for the treatment of skin. Journal of Cosmetic and Laser Therapy, 7(3-4), 177–189. https://doi.org/10.1080/14764170500344575
8. Cordero, R. J. B., & Casadevall, A. (2020). Melanin. Current Biology,30(4), R142–R143. https://doi.org/10.1016/j.cub.2019.12.042

9. Dong, Z., Gong, H., Gao, M., Zhu, W., Sun, X., Feng, L., Fu, T., Li, Y., & Liu, Z. (2016). Polydopamine nanoparticles as a versatile molecular loading platform to enable imaging-guided cancer combination therapy. Theranostics, 6(7), 1031–1042. https://doi.org/10.7150/thno.14431
10. Eom, T., Woo, K., Cho, W., Heo, J. E., Jang, D., Shin, J. I., Martin, D. C., Wie, J. J., & Shim, B. S. (2017). Nanoarchitecturing of natural melanin nanospheres by layer-by-layer assembly: Macroscale anti-inflammatory conductive coatings with optoelectronic tunability. Biomacromolecules, 18(6), 1908–1917. https://doi.org/10.1021/acs.biomac.7b00336
11. Ju, K. Y., Lee, J. W., Im, G. H., Lee, S., Pyo, J., Park, S. B., Lee, J.H., & Lee, J. K. (2013). Bio-inspired, melanin-likenanoparticles as a highly efficient contrast agent for T1-weighted magnetic resonance imaging. Biomacromolecules, 14(10), 3491–3497. https://doi.org/10.1021/bm4008138
12. Kang, S., Baskaran, R., Ozlu, B., Davaa, E., Kim, J. J., Shim, B. S., & Yang, S. G. (2020). T(1)-Positive Mn(2+)-Doped multi-stimuli responsive poly(L-DOPA) nanoparticles for photothermal and photodynamic combination cancer therapy. Biomedicines, 8(10), 417. https://doi.org/10.3390/biomedicines8100417
13. Liu, Y., & Simon, J. D. (2003). The effect of preparation procedures on the morphology of melanin from the ink sac of Sepia officinalis. Pigment Cell Research, 16(1), 72–80. https://doi.org/10.1034/j.1600-0749.2003.00009.x
14. Mavridi-Printezi, A., Menichetti, A., Mordini, D., & Montalti, M. (2023). Functionalization of and through melanin: Strategies and bio-applications. International Journal of Molecular Sciences, 24(11), 9689. https://doi.org/10.3390/ijms24119689
15. Miao, Z. H., Wang, H., Yang, H., Li, Z. L., Zhen, L., & Xu, C. Y. (2015). Intrinsically Mn2+-chelated polydopamine nanoparticles for simultaneous magnetic resonance imaging and photothermal ablation of cancer cells. ACS Applied Materials & Interfaces, 7(31), 16946–16952. https://doi.org/10.1021/acsami.5b06265
16. Obukhova, T., Semenenko, M., Dusheiko, M., Davidenko, S., Davidenko, Y. S., Davidenko, S. S., Malyuta, S., Shahan, S., Pylypchuk, O. S., Mochuk, P., Voitovyсh, M., Kuzmenko, T., & Sarikov, A. (2025). Optical studies of melanin films as a material for solar light absorbers. Materials Research Express, 12(2), 025401. https://doi.org/10.1088/2053-1591/ade227
17. Solano, F. (2017). Melanin and melanin-related polymers as materials with biomedical and biotechnological applications—Cuttlefish ink and mussel foot proteins as inspired biomolecules. International Journal of Molecular Sciences, 18(7), 1561. https://doi.org/10.3390/ijms18071561
18. Stolik, S., Delgado, J. A., Perez, A., & Anasagasti, L. (2000). Measurement of the penetration depths of red and near infrared light in human "ex vivo" tissues. Journal of Photochemistry and Photobiology B: Biology, 57(2-3), 90–93. https://doi.org/10.1016/s1011-1344(00)00082-8
19. Sun, J., Xu, W., Li, L., Fan, B., Peng, X., Qu, B., Wang, L., Li, T., Li, S., & Zhang, R. (2018). Ultrasmall endogenous biopolymer nanoparticles for magnetic resonance/photoacoustic dual-modal imaging-guided photothermal therapy. Nanoscale, 10(22), 10584–10595. https://doi.org/10.1039/c8nr01215f
20. Umur, E., Arslan, F., Bakay, E., Sirek, B., Ayan, B., Baysoy, E., Topaloğlu, N., & Kaleli-Can, G. (2024). Layer-by-layer assembled melanin nanoparticles thin films for photodynamic activity-based disinfection by ultraviolet A irradiation. Emergent Materials, 7, 1259–1270. https://doi.org/10.1007/s42247-024-00761-7
21. Xu, W., Sun, J., Li, L., Peng, X., Zhang, R., & Wang, B. (2017). Melanin-manganese nanoparticles with ultrahigh efficient clearance in vivo for tumor-targeting T1 magnetic resonance imaging contrast agent. Biomaterials Science, 6(1), 146–155. https://doi.org/10.1039/c7bm00635g
22. Zou, Y., Wu, T., Li, N., Guo, X., & Li, Y. (2020). Photothermal-enhanced synthetic melanin inks for near-infrared imaging. Polymer, 186, 122042. https://doi.org/10.1016/j.polymer.2019.122042