We report the encapsulation of the hydrophilic model molecule calcein in the Zr-based MOF UiO-66, followed by amorphization of the framework by ball-milling. We show controlled release of calcein over more than 30 days, compared with the 2 day release period from crystalline UiO-66.

SummaryThe 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.

We have used a family of Zr-based metal–organic frameworks (MOFs) with different functionalized (bromo, nitro and amino) and extended linkers for drug delivery.

The pathway of internalization and final fate of a specific metal-organic framework (MOF) in cells has been investigated for the first time. This study is based on two calcein-loaded UiO-66 samples with particle sizes of 150 and 260 nm (i.e., cal@150 UiO-66 and cal@260 UiO-66, respectively), and shows that the active trafficking of cal@150 UiO-66 is done almost exclusively through clathrin-mediated endocytosis, whereas the uptake of cal@260 UiO-66 is a combination of both clathrin and caveolae-mediated endocytosis. Colocalization studies with a lysosomal marker showed that cal@150 UiO-66 is located mostly in lysosomes for further degradation, whereas cal@260 UiO-66 seems to avoid the lysosomal degradation and potentially deliver the cargo molecules in the cytosol, allowing their distribution to different cellular organelles. This study reveals the importance of the internalization processes of MOFs, particularly the relevance of their particle size, and also the critical significance of their final fate to become an efficient drug delivery system. Based on these results, it is possible that extremely small particle-sized MOFs are not the most efficient carriers and instead relatively medium-sized particles are required.

A critical bottleneck for the use of metal–organic frameworks (MOFs) as drug delivery systems has been allowing them to reach their intracellular targets without being degraded in the acidic environment of the lysosomes. Cells take up particles by endocytosis through multiple biochemical pathways, and the fate of these particles depends on these routes of entry. Here, we show the effect of functional group incorporation into a series of Zr-based MOFs on their endocytosis mechanisms, allowing us to design an efficient drug delivery system. In particular, naphthalene-2,6-dicarboxylic acid and 4,4′-biphenyldicarboxylic acid ligands promote entry through the caveolin-pathway, allowing the particles to avoid lysosomal degradation and be delivered into the cytosol and enhancing their therapeutic activity when loaded with drugs.