Design of a functionalized metal-organic framework system for enhanced targeted delivery to mitochondria

Haddad, S., Abanades Lazaro, I., Fantham, M., Mishra, A., Silvestre-Albero, J., Osterrieth, J. W.M., Kaminski Schierle, G. S., Kaminski, C. F., Forgan, R. F. and Fairen-Jimenez, D. (2020) Design of a functionalized metal-organic framework system for enhanced targeted delivery to mitochondria. Journal of the American Chemical Society, 142(14), pp. 6661-6674. (doi: 10.1021/jacs.0c00188) (PMID:32182066) (PMCID:PMC7146860)

Abstract

Mitochondria play a key role in oncogenesis and constitute one of the most important targets for cancer treatments. Although the most effective way to deliver drugs to mitochondria is by covalently linking them to a lipophilic cation, the in vivo delivery of free drugs still constitutes a critical bottleneck. Herein, we report the design of a mitochondria-targeted metal-organic framework (MOF) that greatly increases the efficacy of a model cancer drug, reducing the required dose to less than 1% compared to the free drug and ca. 10% compared to the non-targeted MOF. The performance of the system is evaluated using a holistic approach ranging from microscopy to transcriptomics. Super-resolution microscopy of MCF-7 cells treated with the targeted MOF system reveals important mitochondrial morphology changes that are clearly associated with cell death as soon as 30 minutes after incubation. Whole transcriptome analysis of cells indicated widespread changes in gene expression when treated with the MOF system, specifically in biological processes that have a profound effect on cell physiology and that are related to cell death. We show how targeting MOFs towards mitochondria represents a valuable strategy for the development of new drug delivery systems.

• Item Type: Articles
• Additional Information: This project has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (NanoMOFdeli), ERC-2016-COG726380 and (SCoTMOF), ERC-2015-STG-677289. D.F.-J. and R.S.F. thank the Royal Society for funding through University Research Fellowships. C.F.K. acknowledges funding from the UK Engineering and Physical Sciences Research Council, EPSRC (grants EP/L015889/1 and EP/H018301/1), the Wellcome Trust (grants 3-3249/Z/16/Z and 089703/Z/09/Z) and the UK Medical Research Council, MRC (grants MR/K015850/1 and MR/K02292X/1), and Infinitus (China) Ltd. We thank EPSRC (grant EP/S009000/1).
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Abanades, Miss Isabel and Forgan, Professor Ross
• Authors: Haddad, S., Abanades Lazaro, I., Fantham, M., Mishra, A., Silvestre-Albero, J., Osterrieth, J. W.M., Kaminski Schierle, G. S., Kaminski, C. F., Forgan, R. F., and Fairen-Jimenez, D.
• College/School: College of Science and Engineering > School of Chemistry
• Journal Name: Journal of the American Chemical Society
• Publisher: American Chemical Society
• ISSN: 0002-7863
• ISSN (Online): 1520-5126
• Published Online: 17 March 2020
• Copyright Holders: Copyright © 2020 American Chemical Society
• First Published: First published in Journal of the American Chemical Society 142(14): 6661-6674
• Publisher Policy: Reproduced under a Creative Commons License