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

Abstract

Metal−organic frameworks (MOFs) have found increasing applications in the biomedical field due to their unique properties and high modularity. Although the limited stability of MOFs in biological environments is increasingly recognized, analytical techniques have not yet been harnessed to their full potential to assess the biological fate of MOFs. Here, we investigate the environment-dependent biochemical transformations of widely researched nanosized MOFs (nMOFs) under conditions relevant to their medical application. We assess the chemical stability of antimicrobial 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 reveal that even a moderate decrease in pH to values encountered in lysosomes (pH 4.5−5) leads to significant dissolution of ZIF-8 and partial dissolution of Ti-MIL-125, whereas no substantial dissolution was observed for TiZr-PCN-415 and Hf-DBA nMOFs. Exposure to phosphate-rich buffers led to phosphate incorporation in all nMOFs, resulting in amorphization and morphological changes. Interestingly, long-term cell culture studies revealed that nMOF (bio)transformations of, e.g., Ti-MIL-125 were cellular compartment-dependent and that the phosphate content in the nMOF varied significantly between nMOFs localized in lysosomes and those in the cytoplasm. These results illustrate the delicate nature and environment-dependent properties of nMOFs across all stages of their life cycle, including storage, formulation, and application, and the need for in-depth analyses of biotransformations for an improved understanding of structure− function relationships. The findings encourage the considerate choice of suspension buffers for MOFs because these media may lead to significant material alterations prior to application.

Cellular Alterations Due to Direct and Indirect Interaction of Nanomaterials with Nucleic Acids

“…Other Nanomaterials 3.5.1. Nanosized-Metal Organic Frameworks (NMOFs) Metal organic frameworks, commonly known as MOFs, have arisen lately as a potential class of materials for diverse applications, such as drug delivery, radio enhancement, imaging or theranostics [104]. MOFs are catalogued as micro-or meso-porous crystalline materials, which consist of metal ions, clusters or chains interconnected by organic linkers [105].…”

“…Although several approaches for overcoming this issue are being implemented, the implications are yet mostly unknown, and their reaction products and transformations are not fully characterized. Thus, this lack of information may have implications in the toxicity and activity of these materials in the biological medium [104]. In this context, Herrmann's laboratory assessed the stability of several NMOFs.…”

“…The behavior of TiZr-PCN NMOFs, which initially showed high stability in different buffers, was of particular interest. However, the partial segregation of Ti and Zr was detected after 2 months of cell culture, which is an issue to be concerned about, since some studies suggest DNA could be a possible intracellular target for Ti [104]. Other studies have also attributed NMOFs toxicity to the solubility and subsequent released metal ions [113].…”