Cellular Uptake, Intracellular Trafficking, and Stability of Biocompatible Metal-Organic Framework (MOF) Particles in Kupffer Cells.

Rapid intracellular degradation of current drug-delivery nanocarriers presents a challenge for achieving ideal controlled drug-release kinetics. Recent in vivo studies have shown that porous hybrid metal-organic frameworks (MOFs), belonging to the Materials of Institute Lavoisier (MIL) family, display prolonged biodegradation behavior. In this study, we investigated stability of these materials in Kupffer cells, a relevant target for the treatment of several life-threatening immune-mediated liver diseases. For this aim, we selected fluorescently labeled microporous MOF particles of MIL88A and MIL88B-NH2, built from trimers of Fe(III) octahedra, as an inorganic component, and fumarate (MIL88A) or 2-amino terephthalate (MIL88B-NH2), as an organic linker. Cell uptake inhibition analysis of MOF particles by a Kupffer cell line (KUP5) has shown that phagocytosis is the major endocytic pathway involved in MIL88B-NH2 internalization. Investigation of MOF interaction with KUP5 cells by real-time microscopy indicated that the structure of MIL88B-NH2 MOFs stays intact up to 15 min after uptake, followed by MOF accumulation in acidic cell compartments and slow degradation, reaching a minimum of 10-15% decomposition over 24 h. MIL88A particles demonstrated similar degradation kinetics. Analysis of the mechanisms of MOF degradation has shown that inhibition of phagosome acidification as well as protease activity does not prevent decomposition of MIL88B-NH2 particles. Thus, our study demonstrates the relative stability of the MOF structure in the phagolysosomal environment of Kupffer cells, revealing potential use of these materials for controlled drug delivery in a case of immune-mediated liver diseases.