Nanoanalytical Insights into the Stability, Intracellular Fate, and Biotransformation of Metal-Organic Frameworks

Metal-organic frameworks (MOFs) have found increasingapplicationsin the biomedical field due to their unique properties and high modularity.Although the limited stability of MOFs in biological environmentsis increasingly recognized, analytical techniques have not yet beenharnessed to their full potential to assess the biological fate ofMOFs. Here, we investigate the environment-dependent biochemical transformationsof widely researched nanosized MOFs (nMOFs) under conditions relevantto their medical application. We assess the chemical stability ofantimicrobial zinc-based drug delivery nMOFs (Zn-ZIF-8 and Zn-ZIF-8:Ce)and radio-enhancer candidate nMOFs (Hf-DBA, Ti-MIL-125, and TiZr-PCN-415)containing biologically nonessential group IV metal ions. We revealthat even a moderate decrease in pH to values encountered in lysosomes(pH 4.5-5) leads to significant dissolution of ZIF-8 and partialdissolution of Ti-MIL-125, whereas no substantial dissolution wasobserved for TiZr-PCN-415 and Hf-DBA nMOFs. Exposure to phosphate-richbuffers led to phosphate incorporation in all nMOFs, resulting inamorphization and morphological changes. Interestingly, long-termcell culture studies revealed that nMOF (bio)transformations of, e.g.,Ti-MIL-125 were cellular compartment-dependent and that the phosphatecontent in the nMOF varied significantly between nMOFs localized inlysosomes and those in the cytoplasm. These results illustrate thedelicate nature and environment-dependent properties of nMOFs acrossall stages of their life cycle, including storage, formulation, andapplication, and the need for in-depth analyses of biotransformationsfor an improved understanding of structure-function relationships.The findings encourage the considerate choice of suspension buffersfor MOFs because these media may lead to significant material alterationsprior to application.