Degradation mechanisms of nanoparticle-based drug delivery systems : the case of polymer conjugate and metal-organic framework

Controlled drug delivery technology has improved medical treatment. A drug delivery system (DDS) should transport and deliver the active molecules progressively with time and at the determined location in the patient body. Nanoparticle-based DDSs have promising abilities to overcome the physiochemical properties of the drug and bypass biological barriers, yielding complete control of the drug delivery process. Nonetheless, the degradation and reactions of nanomaterials in biological media are still burning questions hampering the clinical translation of nanoparticles (NPs). Here, we investigate the degradation process in biological-mimicking media of two types of nanocarriers made of polymer and metal-organic framework. Various characterization techniques are used with a particular focus on nuclear magnetic resonance (NMR) spectroscopy.
First, we described a new approach to preparing polymer-drug conjugate NPs and studied their degradation. Following base-catalyzed ester hydrolysis and bulk erosion, poly(lactic acid)-itaconate PLA-ITA NPs at physiological pH degraded into different oligomers of lactate and itaconate. Liquid NMR spectroscopy and mass spectrometry determined the nature and quantity of water-soluble reaction products and residual polymer. Electron microscopy gave information on the size and morphology of NPs during their degradation. The discovery of slow degradation, hence slow drug release of PLA-ITA NPs, gives suggestions for better design of pH-responsive DDSs.
Second, we conducted an in-depth investigation on the degradation of two nanoMOFs (metal-organic framework NPs), nanoMIL-100(Al) and nanoMIL-100(Fe), in phosphate buffer at pH 7.4. Using a multiscale analysis, we found a stepwise degradation mechanism in which phosphate successively substitutes water and trimesate ligand of nanoMOF, leading to the formation of aluminum/iron phosphate and the release of free trimesate ligands. The role of phosphate was proved by liquid NMR and X-ray photon electron spectroscopy. The degraded nanoMIL-100 particles were analyzed by solid NMR and X-ray absorption near edge (XANES) spectroscopy. Furthermore, the size, morphology, and surface roughness of MIL-100 NPs were monitored during degradation by small-angle X-ray scattering (SAXS) and electron microscopy (TEM and SEM), supporting information on different erosion processes of aluminum- and iron-based MOFs. The molecular motions of water in the nanoMOF aqueous suspension were studied by NMR relaxometry to probe how the degradation changes the interior and exterior surface of nanoMOF. Additionally, the degradation of drug-loaded and surface-coated nanoMOF with phosphate-bearing molecules was demonstrated as a function of metal-ligand complexing strength. The obtained knowledge about nanoMIL-100 degradation contributes to nanoMOF chemistry and lays the basis for further degradation study in complex scenarios.
Finally, an in situ NMR spectroscopy method was set up to track the degradation of NPs without separating them from their suspension. It delivered both qualitative and quantitative information about the nanoMIL-100(Al) degradation. The kinetics of liquid-phase trimesate release and solid-phase trimesate loss were simultaneously determined. Coordination of aluminum with phosphate was also detected, consistent with the proposed degradation mechanism. The established method was then applied to the paramagnetic nanoMIL-100(Fe) and the drug-loaded nanoMIL-100(Al). The presented in situ NMR method offers an option for accurate characterization of NPs’ dynamic processes without altering the reaction medium.
Overall, the blend of analytical methods used in this thesis contributed some knowledge on the degradation mechanisms of polymer and metal-organic framework materials, along with examples of using NMR spectroscopy to characterize DDSs.