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.

Identifying Differing Intracellular Cargo Release Mechanisms by Monitoring In Vitro Drug Delivery from MOFs in Real Time

“… 1 , 2 , 3 , 4 , 5 , 6 The ability to control particle size, 7 , 8 , 9 surface chemistry, 10 and internal porosity 11 , 12 has led to increasingly complex MOF-based materials. These have been designed to target specific cells 13 and organelles, 14 transport large specialized cargo such as oligonucleotides and proteins, 15 , 16 , 17 , 18 , 19 release these in response to specific stimuli, 20 , 21 and combine drug delivery with other techniques such as imaging 22 , 23 , 24 , 25 , 26 or photodynamic therapy. 27 , 28 Despite this diversification of material, the process of postsynthetic drug loading itself is often undercharacterized; cargo is often simply assumed to penetrate the porosity of the MOF despite potential competition from loading solvents.…”

Metal–Organic Framework Composites for Theragnostics and Drug Delivery Applications

“…extended on this idea by conjugating the lipophilic cation triphenylphosphonium (TPP) to UiO‐66(Zr) for direct targeting of the mitochondria in cells. [ 117 ] The authors demonstrate dichloroacetate (DCA) delivery in MCF‐7 breast cancer cells in a rare example of intracellular targeting using MOFs.…”

Applications of nanoscale metal–organic frameworks as imaging agents in biology and medicine

“…The well-known low-toxic luminescent organic dye calcein (cal) has often been employed as a model drug in order to determine the cell internalization and drug delivery potential of MOF nanoparticles. 69,[82][83][84] Calcein is a hydrophilic fluorophore that is unable to cross cell membranes in significant quantities; rather the fluorescent molecule needs a drug delivery system (DDS) to facilitate its transport. In addition, calcein has a self-quenching nature at high concentrations that makes the vesicles carrying high local concentrations of calcein undetectable by fluorescent microscopy.…”

“…In another study, Haddad et al utilized calcein to track the mitochondria targeting efficiencies of UiO-66 nanoparticles loaded with cancer drug dichloroacetate (DCA) and functionalized with a triphenylphosphonium (TPP) targeting unit, 69 which is a lipophilic cation that accumulates in mitochondria as a consequence of the mitochondrial membrane potential in living cells. 65 They reported that MCF-7 human breast cancer cells treated with the targeted MOF system, cal-TPP@(DCA5-UiO-66) demonstrated changes in mitochondrial morphology from elongated and reticular networks (untreated cells, Fig.…”

“…The presence of the MOF in the cells could be ascertained by the green fluorescence of the calcein. 69 Copyright (2020) American Chemical Society.…”