Design of a Functionalized Metal-Organic Framework System for Enhanced Targeted Delivery to Mitochondria.

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 nontargeted 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 min after incubation. Whole transcriptome analysis of cells indicates 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 toward mitochondria represents a valuable strategy for the development of new drug delivery systems.

• Authors: Salame Haddad, Isabel Abánades Lázaro, Marcus Fantham, Ajay Mishra, Joaquin Silvestre-Albero, Johannes W M Osterrieth, Gabriele S Kaminski Schierle, Clemens F Kaminski, Ross S Forgan, David Fairen-Jimenez
• Journal: Journal of the American Chemical Society (J Am Chem Soc) Vol. 142 Issue 14 Pg. 6661-6674 (04 08 2020) ISSN: 1520-5126 [Electronic] United States
• PMID: 32182066 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Metal-Organic Frameworks

Topics

• Drug Delivery Systems (methods)
• Humans
• Metal-Organic Frameworks (metabolism)
• Mitochondria (metabolism)