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

Overview

Journal J Am Chem Soc

Publisher American Chemical Society

Specialty Chemistry

Date 2020 Mar 18

PMID 32182066

Citations 26

Authors

Salame Haddad

Isabel Abanades Lazaro

Marcus Fantham

Ajay Mishra

Joaquin Silvestre-Albero

Johannes W M Osterrieth

Gabriele S Kaminski Schierle

Clemens F Kaminski

Ross S Forgan

David Fairen-Jimenez

Affiliations

Soon will be listed here.

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 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.

Citing Articles

Mitochondrial-targeted therapies in traumatic brain injury: From bench to bedside.

Tabassum S, Wu S, Lee C, Yang B, Gusdon A, Choi H Neurotherapeutics. 2024; 22(1):e00515.

PMID: 39721917 PMC: 11840356. DOI: 10.1016/j.neurot.2024.e00515.

MOFs for next-generation cancer therapeutics through a biophysical approach-a review.

Shano L, Karthikeyan S, Kennedy L, Chinnathambi S, Pandian G Front Bioeng Biotechnol. 2024; 12:1397804.

PMID: 38938982 PMC: 11208718. DOI: 10.3389/fbioe.2024.1397804.

Enhancing Drug Delivery Efficacy Through Bilayer Coating of Zirconium-Based Metal-Organic Frameworks: Sustained Release and Improved Chemical Stability and Cellular Uptake for Cancer Therapy.

Liu X, Obacz J, Emanuelli G, Chambers J, Abreu S, Chen X Chem Mater. 2024; 36(8):3588-3603.

PMID: 38681089 PMC: 11044268. DOI: 10.1021/acs.chemmater.3c02954.

Mitochondrial diseases and mtDNA editing.

Song M, Ye L, Yan Y, Li X, Han X, Hu S Genes Dis. 2024; 11(3):101057.

PMID: 38292200 PMC: 10825299. DOI: 10.1016/j.gendis.2023.06.026.

Research progress in mitochondrial gene editing technology.

Wang Y, Wang Y, Chen Y, Yan Q, Lin A Zhejiang Da Xue Xue Bao Yi Xue Ban. 2023; 52(4):460-472.

PMID: 37643980 PMC: 10495247. DOI: 10.3724/zdxbyxb-2023-0129.

References

Pirnia F, Schneider E, Betticher D, Borner M . Mitomycin C induces apoptosis and caspase-8 and -9 processing through a caspase-3 and Fas-independent pathway. Cell Death Differ. 2002; 9(9):905-14. DOI: 10.1038/sj.cdd.4401062. View

Armstrong J . Mitochondrial medicine: pharmacological targeting of mitochondria in disease. Br J Pharmacol. 2007; 151(8):1154-65. PMC: 2189819. DOI: 10.1038/sj.bjp.0707288. View

Szklarczyk D, Franceschini A, Wyder S, Forslund K, Heller D, Huerta-Cepas J . STRING v10: protein-protein interaction networks, integrated over the tree of life. Nucleic Acids Res. 2014; 43(Database issue):D447-52. PMC: 4383874. DOI: 10.1093/nar/gku1003. View

Abanades Lazaro I, Haddad S, Rodrigo-Munoz J, Marshall R, Sastre B, Del Pozo V . Surface-Functionalization of Zr-Fumarate MOF for Selective Cytotoxicity and Immune System Compatibility in Nanoscale Drug Delivery. ACS Appl Mater Interfaces. 2018; 10(37):31146-31157. DOI: 10.1021/acsami.8b11652. View

Biswas S, Dodwadkar N, Deshpande P, Torchilin V . Liposomes loaded with paclitaxel and modified with novel triphenylphosphonium-PEG-PE conjugate possess low toxicity, target mitochondria and demonstrate enhanced antitumor effects in vitro and in vivo. J Control Release. 2012; 159(3):393-402. PMC: 3348446. DOI: 10.1016/j.jconrel.2012.01.009. View

Wu M, Yang Y . Metal-Organic Framework (MOF)-Based Drug/Cargo Delivery and Cancer Therapy. Adv Mater. 2017; 29(23). DOI: 10.1002/adma.201606134. View

Wieder T, Essmann F, Prokop A, Schmelz K, Schulze-Osthoff K, Beyaert R . Activation of caspase-8 in drug-induced apoptosis of B-lymphoid cells is independent of CD95/Fas receptor-ligand interaction and occurs downstream of caspase-3. Blood. 2001; 97(5):1378-87. DOI: 10.1182/blood.v97.5.1378. View

Orellana-Tavra C, Baxter E, Tian T, Bennett T, Slater N, Cheetham A . Amorphous metal-organic frameworks for drug delivery. Chem Commun (Camb). 2015; 51(73):13878-81. DOI: 10.1039/c5cc05237h. View

Ni K, Lan G, Veroneau S, Duan X, Song Y, Lin W . Nanoscale metal-organic frameworks for mitochondria-targeted radiotherapy-radiodynamic therapy. Nat Commun. 2018; 9(1):4321. PMC: 6193046. DOI: 10.1038/s41467-018-06655-7. View

10.

Shutt T, McBride H . Staying cool in difficult times: mitochondrial dynamics, quality control and the stress response. Biochim Biophys Acta. 2012; 1833(2):417-24. DOI: 10.1016/j.bbamcr.2012.05.024. View

11.

Wang H, Mahle J, Tovar T, Peterson G, Hall M, DeCoste J . Solid-Phase Detoxification of Chemical Warfare Agents using Zirconium-Based Metal Organic Frameworks and the Moisture Effects: Analyze via Digestion. ACS Appl Mater Interfaces. 2019; 11(23):21109-21116. DOI: 10.1021/acsami.9b04927. View

12.

Simon-Yarza M, Baati T, Paci A, Lesueur L, Seck A, Chiper M . Antineoplastic busulfan encapsulated in a metal organic framework nanocarrier: first in vivo results. J Mater Chem B. 2020; 4(4):585-588. DOI: 10.1039/c5tb02084k. View

13.

Gogvadze V, Orrenius S, Zhivotovsky B . Mitochondria as targets for cancer chemotherapy. Semin Cancer Biol. 2008; 19(1):57-66. DOI: 10.1016/j.semcancer.2008.11.007. View

14.

Lucena F, de Araujo L, do D Rodrigues M, da Silva T, Pereira V, Militao G . Induction of cancer cell death by apoptosis and slow release of 5-fluoracil from metal-organic frameworks Cu-BTC. Biomed Pharmacother. 2013; 67(8):707-13. DOI: 10.1016/j.biopha.2013.06.003. View

15.

Tomas-Gamasa M, Martinez-Calvo M, Couceiro J, Mascarenas J . Transition metal catalysis in the mitochondria of living cells. Nat Commun. 2016; 7:12538. PMC: 5023949. DOI: 10.1038/ncomms12538. View

16.

Zielonka J, Joseph J, Sikora A, Hardy M, Ouari O, Vasquez-Vivar J . Mitochondria-Targeted Triphenylphosphonium-Based Compounds: Syntheses, Mechanisms of Action, and Therapeutic and Diagnostic Applications. Chem Rev. 2017; 117(15):10043-10120. PMC: 5611849. DOI: 10.1021/acs.chemrev.7b00042. View

17.

Morris W, Wang S, Cho D, Auyeung E, Li P, Farha O . Role of Modulators in Controlling the Colloidal Stability and Polydispersity of the UiO-66 Metal-Organic Framework. ACS Appl Mater Interfaces. 2017; 9(39):33413-33418. DOI: 10.1021/acsami.7b01040. View

18.

He C, Lu K, Liu D, Lin W . Nanoscale metal-organic frameworks for the co-delivery of cisplatin and pooled siRNAs to enhance therapeutic efficacy in drug-resistant ovarian cancer cells. J Am Chem Soc. 2014; 136(14):5181-4. PMC: 4210117. DOI: 10.1021/ja4098862. View

19.

Zhou H, Fu C, Chen X, Tan L, Yu J, Wu Q . Mitochondria-targeted zirconium metal-organic frameworks for enhancing the efficacy of microwave thermal therapy against tumors. Biomater Sci. 2018; 6(6):1535-1545. DOI: 10.1039/c8bm00142a. View

20.

Bonnet S, Archer S, Allalunis-Turner J, Haromy A, Beaulieu C, Thompson R . A mitochondria-K+ channel axis is suppressed in cancer and its normalization promotes apoptosis and inhibits cancer growth. Cancer Cell. 2007; 11(1):37-51. DOI: 10.1016/j.ccr.2006.10.020. View