Guest Leakage from ZIF-8 Particles under Drug Delivery Conditions: Quantitative Characterization and Guest-Induced Framework Stabilization

Abstract

Metal−organic frameworks (MOFs) are promising nanomaterials for the construction of stimuli−responsive drug delivery platforms. The counterpart of the incredible sensitivity of MOFs to pathological conditions, which underpins targeted drug release, is the significant instability of nanoparticles even in normal physiological media. We report a new experimental approach for quantitative characterization of the guest release profile from MOF ZIF-8 (zeolitic imidazolate framework) suspensions under drug delivery conditions. For this sake, we used ZIF-8 with encapsulated stable nitroxides, which was exposed to physiological media, and the in situ kinetics of guest escape was monitored by electron paramagnetic resonance (EPR). The release of spin probes drastically changes the EPR spectral shapes, thus allowing quantitative characterization of leaked species. We demonstrate that the guest release from ZIF-8 particles in blood-mimicking solutions is a concentration-dependent process dictated by albumin, and nearly full guest release from nanoparticles in fetal bovine serum (FBS) occurs within a few minutes. Significant deceleration of this process and stabilization of ZIF-8 in FBS can be achieved by additional adsorption of guest inhibitors (exemplified by aromatic hydrocarbons) prior to contact with physiological media. The proposed methodology provides further perspectives for optimization of MOF-based platforms for efficient drug delivery.

Stability of ZIF-8 Nanoparticles in Most Common Cell Culture Media

“…The initial suspension of R@ZIF-8, with about 6.5 mg/mL concentration, demonstrates a significantly broadened spectrum with three overlapping lines ( Figure 2 , top trace). We have previously shown that the EPR line broadening for probes inside highly-loaded ZIF-8 is caused by the exchange and dipolar interactions between the radicals located in the same or neighboring cavities of ZIF-8 [ 43 ].…”

“…These results confirm the previously-described degradation of ZIF-8 particles in the presence of buffer components [ 42 , 44 ]. We have previously shown that the release of cargo from ZIF-8 in buffer-containing solutions is a concentration-dependent process [ 43 ]. Therefore, the concentrations of buffer components should be carefully considered when studying the ZIF-8 stability in culture media.…”

“…In addition, most culture media require supplementation with 10% fetal bovine serum (FBS). Previously, it was shown that ZIF-8 undergoes decomposition in the FBS [ 43 ]. However, in this work, we observed only a minor release of cargo (~10%) in the presence of 10% FBS.…”

“…It is known that ZIF-8 particles are rather unstable in serum and most common buffers [ 42 , 43 , 44 ]. At the same time, culture media contain various components that may also have significant effects on the stability of ZIF-8.…”

“…Recently we proposed a new approach for quantitatively probing the extent and rate of guest release from ZIF-8 particles directly under hands-on conditions by EPR [ 43 ]. Tracking the cargo leakage from ZIF-8 upon dissolution of the framework was carried out using a nitroxide spin probe.…”