(368e) Synthesis of Metal-Organic Frameworks (MOFs) and Evaluation of Their Toxicological Profiles.

Metal-organic frameworks (MOFs), materials under the nanotechnology umbrella, are hybrids formed through the combination of metal ions and organic linkers^1,2. The integration of these two constituents allows for tunable porosity, biocompatibility, adaptable shape, high thermal stability and surface area^1,3,4 to be introduced at their synthesis to subsequently result in controlled structure and physicochemical characteristics that make them attractive to be employed in a variety of applications from gas storage^5,6,7, to catalysis^{8,9, 10}, and drug delivery^11,12,13,14 as well as contrast agents for bioimaging^15,16,17.

The exposure and implementation of MOFs however needs to be evaluated because of possible antagonistic interactions of such frameworks with given biosystems. For instance, Su et al. utilized in vitro toxicity evaluations to assess the cytotoxic effects of medi-MOF-1. Pancreatic cancer cells (BxPC-3) were exposed to the MOFs and assessed using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Results showed that there was a cell growth inhibition in a dose-dependent manner, specifically, exposure to 50 µg/ml MOFs caused the highest levels of cell death¹⁸. Chen et al., exposed MIL-160(Fe) MOFs to human normal liver and hepatocellular carcinoma cells. A decrease in cell viability in dose-dependent manner was observed and the cause of toxicity was due to the MOFs’ metal component¹⁹. While these in vitro toxicity studies helped correlate toxicological pathways function of both MOFs’ physicochemical characteristics and their synthesis method cyto- and genotoxic effects and their possible synergism in how they account for homeostatic cellular changes have been sparse. Moreover, the ability to identify any cell generational transformation and propagation of such transformation upon framework exposure is currently lacking. Further, in vivo toxicity evaluations were focused on limited MOFs and only revealed weak mechanistic analysis or minimal toxicological pathways identification. Without such correlations and analysis, framework deleterious effects (when individual or when in synthesized structures) are difficult to assess and control. As such, lack of analysis and evaluation of toxicological profiles could jeopardize the implementation of the frameworks in consumer applications.

This project aims to investigate the toxicological profiles of selected MOFs and their thin films to determine mechanisms of toxicity before consumer implementation. The objective is to contribute to the understanding of MOFs deleterious effects, both using cyto- and genotoxic approaches as well as real-time, high throughput strategies. The proposed methods involve synthesizing and characterizing selected MOFs and their thin films and exposing such frameworks and films to human epithelial cells, where the lung cells serve as model for the toxicity of target system (i.e., lungs). Prior to exposure, the MOFs/thin films are characterized by microscopical and spectroscopical techniques to determine their physicochemical characteristics. Subsequently, upon exposure frameworks, films and cell systems are investigated using both microscopy and cellular assay. Our results show that the frameworks affect cells in a dose-dependent manner with such effects being function of the materials’ physico-chemical properties. Possible mechanisms responsible for cell toxicity are also derived from systems characteristics. Such studies could not only lead to rationale, safe-by-design strategies development of nanomaterials and nanomaterials films for biotechnological implementation but further, could also allow for user-controlled implementation of such structures.

References:

(1) Lin, W. X.; Hu, Q.; Yu, J. C.; Jiang, K.; Yang, Y. Y.; Xiang, S. C.; Cui, Y. J.; Yang, Y.; Wang, Z. Y.; Qian, G. D. Low Cytotoxic Metal-Organic Frameworks as Temperature-Responsive Drug Carriers. Chempluschem 2016, 81 (8), 804-810, Article. DOI: 10.1002/cplu.201600142.

(2) Tamames-Tabar, C.; Cunha, D.; Imbuluzqueta, E.; Ragon, F.; Serre, C.; Blanco-Prieto, M. J.; Horcajada, P. Cytotoxicity of nanoscaled metal-organic frameworks. Journal of Materials Chemistry B 2014, 2 (3), 262-271, Article. DOI: 10.1039/c3tb20832j.

(3) Yang, B. C.; Shen, M.; Liu, J. Q.; Ren, F. Post-Synthetic Modification Nanoscale Metal-Organic Frameworks for Targeted Drug Delivery in Cancer Cells. Pharmaceutical Research 2017, 34 (11), 2440-2450, Article. DOI: 10.1007/s11095-017-2253-9.

(4) Lucena, M. A. M.; Oliveira, M. F. L.; Arouca, A. M.; Talhavini, M.; Ferreira, E. A.; Alves, S.; Veiga-Souza, F. H.; Weber, I. T. Application of the Metal-Organic Framework Eu(BTC) as a Luminescent Marker for Gunshot Residues: A Synthesis, Characterization, and Toxicity Study. Acs Applied Materials & Interfaces 2017, 9 (5), 4684-4691, Article. DOI: 10.1021/acsami.6b13474.

(5) Kayal, S.; Sun, B. C.; Chakraborty, A. Study of metal-organic framework MIL-101(Cr) for natural gas (methane) storage and compare with other MOFs (metal-organic frameworks). Energy 2015, 91, 772-781, Article. DOI: 10.1016/j.energy.2015.08.096.

(6) Gutov, O. V.; Bury, W.; Gomez-Gualdron, D. A.; Krungleviciute, V.; Fairen-Jimenez, D.; Mondloch, J. E.; Sarjeant, A. A.; Al-Juaid, S. S.; Snurr, R. Q.; Hupp, J. T.; et al. Water-Stable Zirconium-Based Metal-Organic Framework Material with High-Surface Area and Gas-Storage Capacities. Chemistry-a European Journal 2014, 20 (39), 12389-12393, Article. DOI: 10.1002/chem.201402895.

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(10) Ling, P. H.; Lei, J. P.; Zhang, L.; Ju, H. X. Porphyrin-Encapsulated Metal-Organic Frameworks as Mimetic Catalysts for Electrochemical DNA Sensing via Allosteric Switch of Hairpin DNA. Analytical Chemistry 2015, 87 (7), 3957-3963, Article. DOI: 10.1021/acs.analchem.5b00001.

(11) Kundu, T.; Mitra, S.; Patra, P.; Goswami, A.; Diaz, D. D.; Banerjee, R. Mechanical Downsizing of a Gadolinium(III)-based Metal-Organic Framework for Anticancer Drug Delivery. Chemistry-a European Journal 2014, 20 (33), 10514-10518, Article. DOI: 10.1002/chem.201402244.

(12) Pan, Y. B.; Wang, S. Q.; He, X. C.; Tang, W. W.; Wang, J. H.; Shao, A. W.; Zhang, J. M. A combination of glioma in vivo imaging and in vivo drug delivery by metal-organic framework based composite nanoparticles. Journal of Materials Chemistry B 2019, 7 (48), 7683-7689, Article. DOI: 10.1039/c9tb01651a.

(13) Orellana-Tavra, C.; Marshall, R. J.; Baxter, E. F.; Lazaro, I. A.; Tao, A.; Cheetham, A. K.; Forgan, R. S.; Fairen-Jimenez, D. Drug delivery and controlled release from biocompatible metal-organic frameworks using mechanical amorphizationt. Journal of Materials Chemistry B 2016, 4 (47), 7697-7707, Article. DOI: 10.1039/c6tb02025a.

(14) Shu, F. P.; Lv, D. J.; Song, X. L.; Huang, B.; Wang, C.; Yu, Y. Z.; Zhao, S. C. Fabrication of a hyaluronic acid conjugated metal organic framework for targeted drug delivery and magnetic resonance imaging. Rsc Advances 2018, 8 (12), 6581-6589, Article. DOI: 10.1039/c7ra12969f.

(15) Taylor, K. M. L.; Rieter, W. J.; Lin, W. B. Manganese-Based Nanoscale Metal-Organic Frameworks for Magnetic Resonance Imaging. Journal of the American Chemical Society 2008, 130 (44), 14358-+, Article. DOI: 10.1021/ja803777x.

(16) Taylor-Pashow, K. M. L.; Della Rocca, J.; Xie, Z. G.; Tran, S.; Lin, W. B. Postsynthetic Modifications of Iron-Carboxylate Nanoscale Metal-Organic Frameworks for Imaging and Drug Delivery. Journal of the American Chemical Society 2009, 131 (40), 14261-+, Article. DOI: 10.1021/ja906198y.

(17) Chowdhuri, A. R.; Bhattacharya, D.; Sahu, S. K. Magnetic nanoscale metal organic frameworks for potential targeted anticancer drug delivery, imaging and as an MRI contrast agent. Dalton Transactions 2016, 45 (7), 2963-2973, Article. DOI: 10.1039/c5dt03736k.

(18) Su, H. M.; Sun, F. X.; Jia, J. T.; He, H. M.; Wang, A. F.; Zhu, G. S. A highly porous medical metal-organic framework constructed from bioactive curcumin. Chemical Communications 2015, 51 (26), 5774-5777, Article. DOI: 10.1039/c4cc10159f.

(19) Chen, G. S.; Leng, X.; Luo, J. Y.; You, L. T.; Qu, C. H.; Dong, X. V.; Huang, H. L.; Yin, X. B.; Ni, J. In Vitro Toxicity Study of a Porous Iron(III) Metal-Organic Framework. Molecules 2019, 24 (7), 14, Article. DOI: 10.3390/molecules24071211.