Abánades Lázaro, I., Haddad, S., Rodrigo-Muñoz, J., Orellana-Tavra, C., del Pozo, V., Fairen-Jimenez, D. and Forgan, R. S. (2018) Mechanistic investigation into the selective anticancer cytotoxicity and immune system response of surface-functionalised, dichloroacetate-loaded, UiO-66 nanoparticles. ACS Applied Materials and Interfaces, 10(6), pp. 5255-5268. (doi: 10.1021/acsami.7b17756) (PMID:29356507)
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Abstract
The high drug loading and excellent biocompatibilities of metal-organic frameworks (MOFs) have led to their application as drug delivery systems (DDSs). Nanoparticle surface chemistry dominates both biostability and dispersion of DDSs while governing their interactions with biological systems, cellular and/or tissue targeting, and cellular internalisation, leading to a requirement for versatile and reproducible surface functionalisation protocols. Herein, we explore not only the effect of introducing different surface functionality to the biocompatible Zr-MOF UiO-66, but also the efficacy of three surface modification protocols: (i) direct attachment of biomolecules (folic acid, biotin) introduced as modulators of UiO-66 synthetic, (ii) our previously reported ‘’click-modulation” approach to covalently attach polymers (poly(ethylene glycol), poly-L-lactide, poly-N-isopropylacrylamide) to the surface of UiO-66 through click chemistry, and (iii) surface ligand exchange, to postsynthetically coordinate folic acid, biotin and heparin to UiO-66. The innovative use of a small molecule with metabolic anticancer activity, dichloroacetic acid (DCA), as a modulator during synthesis is described, and found to be compatible with all three protocols, yielding surface-coated, DCA-loaded (10-20% w/w) nanoMOFs (70-170 nm). External surface modification generally enhances stability and colloidal dispersion of UiO-66. Cellular internalisation routes and efficiencies of UiO-66 by HeLa cervical cancer cells can be tuned by surface chemistry, and anticancer cytotoxicity of DCA-loaded MOFs correlates with endocytosis efficiency and mechanisms. The MOFs with the most promising coatings (folic acid, poly(ethylene glycol), poly-L-lactide, and poly-N-isopropylacrylamide) were extensively tested for selectivity of anti-cancer cytotoxicity against MCF-7 breast cancer cells and HEK293 healthy kidney cells, as well as for cell proliferation and ROS production against J774 macrophages and peripheral blood lymphocytes (PBLs) isolated from the blood of human donors. DCA-loaded, folic acid modified UiO-66 selectively kills cancer cells without harming healthy ones or provoking immune system response in vitro, suggesting a significant targeting effect and great potential in anticancer drug delivery. The results provide mechanistic insight into the design and functionalisation of MOFs for drug delivery, and underline the availability of various in vitro techniques to potentially minimise early-stage in vivo animal studies, following the three Rs: reduction, refinement and replacement.
| Item Type: | Articles |
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| Additional Information: | This project received funding in part from the European Research Council (ERC) under the European Union's Horizon 2020 Programme for Research and Innovation (grant agreement no. 677289, SCoTMOF, ERC2015-STG). |
| Status: | Published |
| Refereed: | Yes |
| Glasgow Author(s) Enlighten ID: | Abanades, Isabel and Forgan, Professor Ross |
| Authors: | Abánades Lázaro, I., Haddad, S., Rodrigo-Muñoz, J., Orellana-Tavra, C., del Pozo, V., Fairen-Jimenez, D., and Forgan, R. S. |
| College/School: | College of Science and Engineering > School of Chemistry |
| Journal Name: | ACS Applied Materials and Interfaces |
| Publisher: | American Chemical Society |
| ISSN: | 1944-8244 |
| ISSN (Online): | 1944-8252 |
| Published Online: | 22 January 2018 |
| Copyright Holders: | Copyright © 2018 American Chemical Society. |
| First Published: | First published in ACS Applied Materials and Interfaces 10(6):5255-5268 |
| Publisher Policy: | Reproduced in accordance with the copyright policy of the publisher |
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