Selective Surface PEGylation of UiO-66 Nanoparticles for Enhanced Stability, Cell Uptake, and pH-Responsive Drug Delivery

Summary

The high storage capacities and excellent biocompatibilities of metal-organic frameworks (MOFs) have made them emerging candidates as drug-delivery vectors. Incorporation of surface functionality is a route to enhanced properties, and here we report on a surface-modification procedure—click modulation—that controls their size and surface chemistry. The zirconium terephthalate MOF UiO-66 is (1) synthesized as ∼200 nm nanoparticles coated with functionalized modulators, (2) loaded with cargo, and (3) covalently surface modified with poly(ethylene glycol) (PEG) chains through mild bioconjugate reactions. At pH 7.4, the PEG chains endow the MOF with enhanced stability toward phosphates and overcome the “burst release” phenomenon by blocking interaction with the exterior of the nanoparticles, whereas at pH 5.5, stimuli-responsive drug release is achieved. The mode of cellular internalization is also tuned by nanoparticle surface chemistry, such that PEGylated UiO-66 potentially escapes lysosomal degradation through enhanced caveolae-mediated uptake. This makes it a highly promising vector, as demonstrated for dichloroacetic-acid-loaded materials, which exhibit enhanced cytotoxicity. The versatility of the click modulation protocol will allow a wide range of MOFs to be easily surface functionalized for a number of applications.

Graphical Abstract

Highlights

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  A surface modification protocol for MOFs compatible with cargo loading is reported

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  PEGylated UiO-66 nanoparticles show pH-responsive cargo release

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  Endocytosis routes are modified by the control of MOF surface chemistry

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  Enhanced cytotoxicity is observed for PEGylated UiO-66 loaded with dichloroacetate

The Bigger Picture

Using artificial agents to deliver drugs selectively to sites of disease while protecting them from metabolism and clearance offers potential routes to new treatments. Porous metal-organic frameworks (MOFs) have emerged as potential candidates because they offer high storage capacities and easy clearance after delivery. We report on a method that controls the size and surface chemistry of MOFs and is compatible with cargo loading, showing that surface modification with biocompatible poly(ethylene glycol) chains improves stability toward phosphate and allows pH-responsive cargo release, which could enhance selectivity because cancerous cells are typically more acidic than healthy ones. Modes of cellular uptake are also altered, which could account for the enhanced cell death when polymer-coated MOFs are loaded with the anticancer drug dichloroacetic acid. Surface modification is mild and could be applied across a range of MOFs, opening up applications in selective molecular separation, blending into hybrids, and turn-on catalysis.

Abstract

Porous nanoparticles that can store drug molecules have great potential in drug delivery, the use of nanocarriers to transport therapeutic agents around the body. Forgan and colleagues report on a method that controls the surface properties and functionality of metal-organic framework nanoparticles to enhance their stability, allow stimuli-responsive release of drug molecules, and enhance the anticancer therapeutic effect of loaded drugs by changing the route of cell uptake. Further development of these materials could enhance drug efficiencies and avoid unwanted side effects.