Neurodegenerative diseases, including Alzheimer’s and Parkinson’s, are linked to an increase in oxidative stress and the excessive production of reactive oxygen species (ROS). This research focuses on how controlled ROS activity and the selective targeting of pathological structures can be used in neurodegenerative disease research. It specifically looks at the use of nanoparticles such as porphyrins and metal-organic framework (MOF)-based photodynamic therapy (PDT). In nanomedicine, the surface, functionality, and biocompatibility of nanocarriers, as well as their ability to penetrate through the blood–brain barrier and interact with specific targets, need to be controlled. To this end, we explored a multimodal approach based on PDT, employing nanoparticles as the key platforms for modulating ROS levels and for enabling selective molecular targeting. Photosensitizers are excited by light to produce a wide array of highly reactive species via either Type I or Type II photochemical reactions. The net accumulation of ROS in neurons would typically be considered to be detrimental. However, when generated under spatial and temporal control, ROS can indeed act to alter conformation and/or to covalently modify pathological structures in an attempt to convert these into more stable and non-disease-promoting forms, all the while limiting excessive damage to surrounding neurons.
MOFs can serve as a nanostructured platform for PDT, where the porous structure, metal-coordination sites, and organic linkers can be engineered to incorporate or deliver photosensitizers. Porphyrin-based drugs, in particular, can serve as a multimodal platform for PDT. We examine here the UiO series of MOFs, and in particular, the MOF based on the UiO-66 structure, and show that the functional groups, photosensitizers, and therapeutic molecules can be delivered and activated in a controlled manner.
Porphyrin derivatives such as zinc and magnesium porphyrins are promising candidates for PDT due to the high tunability of their electronic properties, their ability to absorb light, and the subsequent generation of ROS in photochemical reactions. In a computational analysis, we analyzed their molecular stability, optimized energy, and electrostatic surface potential for their efficiency.
References
Gough, D. R., & Cotter, T. G. (2011). Hydrogen peroxide: A Jekyll and Hyde signalling molecule. Cell Death & Disease, 2(10), e213.
Beta-amyloid and the amyloid hypothesis. (2017, March). Alzheimer’s Association.
O’Brien, R. J., & Wong, P. C. (2011). Amyloid precursor protein processing and Alzheimer’s disease. Annual Review of Neuroscience, 34(1), 185–204.
Pulawski, W., Ghoshdastider, U., Andrisano, V., & Filipek, S. (2012). Ubiquitous amyloids. Applied Biochemistry and Biotechnology, 166(7), 1626–1643.
Singh, S. K., Srivastav, S., Yadav, A. K., Srikrishna, S., & Perry, G. (2016). Overview of Alzheimer’s disease and some therapeutic approaches targeting Aβ by using several synthetic and herbal compounds. Oxidative Medicine and Cellular Longevity, 2016, 1–22.
Mohandas, E., Rajmohan, V., & Raghunath, B. (2009). Neurobiology of Alzheimer’s disease. Indian Journal of Psychiatry, 51(1), 55.
Mudher, A., & Lovestone, S. (2002). Alzheimer’s disease—Do tauists and baptists finally shake hands? Trends in Neurosciences, 25(1), 22–26.
Arcuri, C., Monarca, L., Ragonese, F., Mecca, C., Bruscoli, S., Giovagnoli, S., Donato, R., Bereshchenko, O., Fioretti, B., & Costantino, F. (2018). Probing internalization effects and biocompatibility of ultrasmall zirconium metal-organic frameworks UiO-66 NP in U251 glioblastoma cancer cells. Nanomaterials, 8(11), 867.
Ahmed, M., Davis, J., Aucoin, D., Sato, T., Ahuja, S., Aimoto, S., Elliott, J. I., Van Nostrand, W. E., & Smith, S. O. (2010). Structural conversion of neurotoxic amyloid-β1–42 oligomers to fibrils. Nature Structural & Molecular Biology, 17(5), 561–567.
Rogge, S. M. J., Yot, P. G., Jacobsen, J., Muniz-Miranda, F., Vandenbrande, S., Gosch, J., Ortiz, V., Collings, I. E., Devautour-Vinot, S., Maurin, G., Stock, N., & Van Speybroeck, V. (2020). Charting the metal-dependent high-pressure stability of bimetallic UiO-66 materials. ACS Materials Letters, 2(4), 438–445.
UiO-66 zirconium building bricks for stable metal organic frameworks. (n.d.). Strem Chemicals.
Hider, R. C., Roy, S., Ma, Y. M., Kong, X. L., & Preston, J. (2011). The potential application of iron chelators for the treatment of neurodegenerative diseases. Metallomics, 3(3), 239–249. doi: 10.1039/c0mt00087f
Hughes, M. (2015, October 29). EDTA chelation: Rise of the undead therapy. Centre for Blood Research, University of British Columbia.
Iron chelator—An overview. (n.d.). ScienceDirect Topics.
Rogge, S. M. J., Yot, P. G., Jacobsen, J., Muniz-Miranda, F., Vandenbrande, S., Gosch, J., Ortiz, V., Collings, I. E., Devautour-Vinot, S., Maurin, G., Stock, N., & Van Speybroeck, V. (2020). Charting the metal-dependent high-pressure stability of bimetallic UiO-66 materials. ACS Materials Letters, 2(4), 438–445.
UiO-66 zirconium building bricks for stable metal organic frameworks. (n.d.). Strem Chemicals.
Dusek, P., Schneider, S. A., & Aaseth, J. (2016). Iron chelation in the treatment of neurodegenerative diseases. Journal of Trace Elements in Medicine and Biology, 38, 81–92. doi: 10.1016/j.jtemb.2016.03.010