Repository logo
 

Zirconium-based metal-organic frameworks as drug delivery systems


Type

Thesis

Change log

Authors

Zhuang, Yunhui 

Abstract

Metal-organic frameworks (MOFs) are highly ordered porous materials made up of metal ions or clusters connected by organic linkers. The ease of surface modification for zirconium-based MOFs allows for a variety of designs for targeted therapeutic delivery. This thesis aims to understand and develop the Zr-based MOFs as a drug delivery system. Firstly, a Zr-based MOF, NU-1000, was examined for its ability to encapsulate and deliver a large hydrophobic drug, fulvestrant, in breast cancer cells. NU-1000 was shown to be internalised by the human breast cancer cell line, MCF-7 cells, within 24 hours of incubation. Fulvestrant loaded NU-1000 reduced cancer cell proliferation and inhibited the expression of oestrogen receptors in MCF-7 cells. Although NU-1000 was able to load fulvestrant without defects in its crystalline structure, potential aggregations were observed, which could interfere MOFs’ colloidal stability for drug delivery applications. In order to improve MOFs' colloidal stability, a panel of Zr-based MOFs were surface functionalised with methoxy polyethylene glycol (mPEG-PO3) followed by lyophilisation. These PEGylated nanoMOFs were able to maintain their hydrodynamic diameter in water and PBS compared to their non-PEGylated counterparts. PEGylated nanoMOFs also reduced cytotoxicity in vitro and were taken up by HeLa cells within 24 hours of incubation. Their ability to load, store and delivery drugs were tested using an anti-cancer drug, doxorubicin, where delayed drug-release capability was observed. Since nanoparticles will almost inevitably be in contact with immune cells in the blood circulation system upon administration, human peripheral blood mononuclear cells were used to gain insights into PEGylated MOFs' interactions with the human immune system. PEGylated NU-901 has shown some toxicity towards monocytes but not in T cells, but no toxicity was observed for PEGylated UiO-66, ZIF-8 and PCN-222. The expression of inflammatory cytokines was also examined, where elevated IL-6 was observed for cells treated with PEGylated ZIF-8, a zinc-based MOFs. In summary, Zr-based MOFs have shown many promises to deliver drugs in vitro. Their colloidal stability and biocompatibility can be significantly improved by controlled coordination of mPEG-PO3. This thesis also presented a comprehensive study on MOFs’ immunotoxicity with human primary immune cells, which offers new insights for their potential clinical applications.

Description

Date

2022-03-31

Advisors

Fairen Jimenez, David

Keywords

Drug delivery, Metal-organic frameworks, Nanoparticles

Qualification

Doctor of Philosophy (PhD)

Awarding Institution

University of Cambridge