Surface-functionalisation of Zr-Fumarate MOF for selective cytotoxicity and immune system compatibility in nanoscale drug delivery

Abánades Lázaro, I., Haddad, S., Rodrigo-Muñoz, J., Marshall, R. J., Sastre, B., del Pozo, V., Fairen-Jimenez, D. and Forgan, R. S. (2018) Surface-functionalisation of Zr-Fumarate MOF for selective cytotoxicity and immune system compatibility in nanoscale drug delivery. ACS Applied Materials and Interfaces, 10(37), pp. 31146-31157. (doi:10.1021/acsami.8b11652) (PMID:30136840)

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Abstract

Metal-organic frameworks (MOFs), network structures wherein metal ions or clusters link organic ligands into porous materials, are being actively researched as nanoscale drug delivery devices (DDSs) as they offer tuneable structures with high cargo loading that can easily be further functionalized for targeting and enhanced physiological stability. The excellent biocompatibility of Zr has meant that its MOFs are amongst the most studied to date, in particular the archetypal Zr terephthalate UiO-66. In contrast, the isoreticular analogue linked by fumarate (Zr-fum) has received little attention, despite the endogenous linker being part of the Krebs cycle. Herein, we report a comprehensive study of Zr-fum in the context of drug delivery. Reducing particle size is shown to increase uptake by cancer cells while reducing internalisation by macrophages, immune system cells that remove foreign objects from the bloodstream. Zr-fum is compatible with defect-loading of the drug dichloroacetate, as well as surface modification during synthesis, through coordination modulation, and postsynthetically. DCA-loaded, PEGylated Zr-fum shows selective in vitro cytotoxicity towards HeLa and MCF-7 cancer cells, likely as a consequence of its enhanced caveolae-mediated endocytosis compared to uncoated precursors, and it is well tolerated by HEK293 kidney cells, J774 macrophages, and human peripheral blood lymphocytes. Compared to UiO-66, Zr-fum is more efficient at transporting the drug mimic calcein into HeLa cells, and DCA-loaded, PEGylated Zr-fum is more effective at reducing HeLa and MCF-7 cell proliferation than the analogous UiO-66 sample. In vitro examination of immune system response shows Zr-fum samples induce less reactive oxygen species than UiO-66 analogues, possibly as a consequence of the linker being endogenous, and do not activate the C3 and C4 complement cascade pathways, suggesting that Zr-fum can avoid phagocytic activation. The results show that Zr-fum is an attractive alternative to UiO-66 for nanoscale drug delivery, and that a wide range of in vitro experiments are available to greatly inform the design of DDSs prior to early stage animal studies.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Abanades, Miss Isabel and Forgan, Dr Ross and Marshall, Mr Ross James
Authors: Abánades Lázaro, I., Haddad, S., Rodrigo-Muñoz, J., Marshall, R. J., Sastre, B., 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:23 August 2018
Copyright Holders:Copyright © 2018 American Chemical Society
First Published:First published in ACS Applied Materials and Interfaces 10(37): 31146-31157
Publisher Policy:Reproduced in accordance with the copyright policy of the publisher
Data DOI:10.5525/gla.researchdata.656

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
689571SCoTMOFRoss ForganEuropean Research Council (ERC)677289SCHOOL OF CHEMISTRY