Nanoscale Iron-Based Metal-Organic Frameworks: Incorporation of Functionalized Drugs and Degradation in Biological Media

Abstract

Metal-organic frameworks (MOFs) attract growing interest in biomedical applications. Among thousands of MOF structures, the mesoporous iron(III) carboxylate MIL-100(Fe) (MIL stands for the Materials of Lavoisier Institute) is among the most studied MOF nanocarrier, owing to its high porosity, biodegradability, and lack of toxicity. Nanosized MIL-100(Fe) particles (nanoMOFs) readily coordinate with drugs leading to unprecedented payloads and controlled release. Here, we show how the functional groups of the challenging anticancer drug prednisolone influence their interactions with the nanoMOFs and their release in various media. Molecular modeling enabled predicting the strength of interactions between prednisolone-bearing or not phosphate or sulfate moieties (PP and PS, respectively) and the oxo-trimer of MIL-100(Fe) as well as understanding the pore filling of MIL-100(Fe). Noticeably, PP showed the strongest interactions (drug loading up to 30 wt %, encapsulation efficiency > 98%) and slowed down the nanoMOFs' degradation in simulated body fluid. This drug was shown to bind to the iron Lewis acid sites and was not displaced by other ions in the suspension media. On the contrary, PS was entrapped with lower efficiencies and was easily displaced by phosphates in the release media. Noticeably, the nanoMOFs maintained their size and faceted structures after drug loading and even after degradation in blood or serum after losing almost the totality of the constitutive trimesate ligands. Scanning electron microscopy with high annular dark field (STEM-HAADF) in conjunction with X-Ray energy-dispersive spectrometry (XEDS) was a powerful tool enabling the unraveling of the main elements to gain insights on the MOF structural evolution after drug loading and/or upon degradation.

Keywords: STEM-HAADF; biodegradable nanoparticle; biological media; drug loading; metal–organic frameworks; prednisolone; stability.

Figure 1

Schematic representation of MIL-100(Fe)’s structure resulting from iron(III) trimers and trimesic acid assembly. The three active molecules, prednisolone, PP, and PS, were encapsulated into the nanoMOFs’ large cages by overnight impregnation.

Figure 2

Pore filling of prednisolone in MIL-100(Fe) revealed by Monte Carlo simulations. The characteristic guest/MOF interacting distances are indicated by the black-dashed line. Color code: C (dark gray), O (red), H (white), and Fe (black). The guest molecules are represented by the light cyan color in (a,b) to clarify the visualization.

Figure 3

DFT-optimized most stable drug@Fe-CUS loading configurations for (a) prednisolone, (b) PP, and (c) PS. Color code: C (brown), O (red), H (white), ion (black), S (yellow), P (purple), and Na (green). The distances are in Å.

Figure 4

STEM-HAADF images of nanoMOFs before (a) and after loading with 19 wt % prednisolone (b), 30 wt % PP (c), and 15 wt % PS (d).

Figure 5

(a) Typical STEM-HAADF images of nanoMOFs loaded with PP at a DL of 30 wt %. (b,c) Elemental distribution of Fe (red) and P (violet) into the nanoMOFs after PP loading. Yellow rectangles represent the selected regions of interest, and the green rectangle corresponds to the quantification of the elements in the entire image. The scale bar represents 200 nm.

Figure 6

(a,d) Typical STEM-HAADF images of nanoMOFs (0.25 mg mL⁻¹) after 48 h incubation in PBS and a media containing equimolar amounts of Na₂SO₄ and Na₂HPO₄. (b,c,e,f) STEM–XEDS elemental analysis of degraded nanoMOFs. P (purple) and S (blue).

Figure 7

(a) Comparison of PP (pink) and PS (green) release in sulfates. (b) Trimesate loss of nanoMOFs with PS (DL = 15 wt %) (dark green) and PP (DL = 30 wt %) (dark red) in sulfate-containing media, pH 7.4, 37 °C. The sample concentration was 0.5 mg mL⁻¹.

Figure 8

STEM-HAADF images of nanoMOFs after incubation in (a,b) serum and blood for 2 h and (c,d) serum and blood for 48 h. The sample concentration was 0.5 mg mL⁻¹.

Figure 9

Upper panel: STEM-HAADF of nanoMOFs after 48 h incubation in blood. Elemental mapping of blood components into the nanoMOFs. Fe (red), P (violet), S (blue), N (white), Ca (yellow), Mg (dark blue), O (brown), and C (green). Lower panel: DFT-calculated interaction energies of ions@Fe-CUS for sodium carbonate, sulfate, and phosphate. Color code: C (brown), O (red), H (white), ion (black), S (yellow), P (purple), and Na (green). Scale bar represents 400 nm, unless stated.