Chitosan-coated mesoporous MIL-100(Fe) nanoparticles as improved bio-compatible oral nanocarriers

Nanometric biocompatible Metal-Organic Frameworks (nanoMOFs) are promising candidates for drug delivery. Up to now, most studies have targeted the intravenous route, related to pain and severe complications; whereas nanoMOFs for oral administration, a commonly used non-invasive and simpler route, remains however unexplored. We propose here the biofriendly preparation of a suitable oral nanocarrier based on the benchmarked biocompatible mesoporous iron(III) trimesate nanoparticles coated with the bioadhesive polysaccharide chitosan (CS). This method does not hamper the textural/structural properties and the sorption/release abilities of the nanoMOFs upon surface engineering. The interaction between the CS and the nanoparticles has been characterized through a combination of high resolution soft X-ray absorption and computing simulation, while the positive impact of the coating on the colloidal and chemical stability under oral simulated conditions is here demonstrated. Finally, the intestinal barrier bypass capability and biocompatibility of CS-coated nanoMOF have been assessed in vitro, leading to an increased intestinal permeability with respect to the non-coated material, maintaining an optimal biocompatibility. In conclusion, the preservation of the interesting physicochemical features of the CS-coated nanoMOF and their adapted colloidal stability and progressive biodegradation, together with their improved intestinal barrier bypass, make these nanoparticles a promising oral nanocarrier.


References
The extent of CS coating on MIL-100(Fe) NPs was quantified by fluorescence spectrometry and TGA. The amount of CS coating on the NPs was indirectly estimated by the difference between the CS concentration in the initial reaction mixture (2.50 ± 0.01 mg·mL -1 ) and the supernatant collected after reaction and subsequent washing steps (0.14 ± 0.03 mg·mL -1 ). These values conclude that 49.1 ± 0.3 wt % of the final coated CS_MIL-100(Fe) NPs corresponds to CS coating. Consequently, a highly efficient CS grafting of 94.4 ± 0.4 % was obtained in only 30 min. of reaction (considering as 100 % the total amount of CS in the initial impregnation conditions).   oligomers. The size of the molecule is indicated for three different orientations.

Estimation of the polymer conformation and density of coating
One can estimate the polymer density using the conformation of the polymer chains on the NP external surface, which is mainly determined by: (i) the distance between grafted CS chains (D) Considering these parameters, there are two main conformations: if the surface density is low (D > R F ) the CS chains adopt a "mushroom" conformation and remain not fully extended away from the NP surface. In case of increased coating densities (D < R F ), the CS chains acquire a "brush" conformation with a thick layer of CS chains extended away from the NP surface.
If the solution is a good solvent for the polymer (i.e. CS in water:ethanol) the Flory radius can Then, the calculated Flory radius is R F ~ 23 nm.
The calculated distance between grafted CS chains is D ~ 3 nm, whereas the Flory radius is R F ~ 23 nm.
Thus, as the distance between CS chains is lower than the Flory radius (D ~ 3 nm < R F ~ 23 nm) and the thickness of the grafted CS layer (L) is of ~ 35 nm (L < calculated length of a CS chain), CS chains are expected to follow a "brush" conformation with partial folding of the polymer.
One could consider that such a conformation of the CS coating may be beneficial to the interaction of the NPs with biological gastrointestinal structures (mucus, enzyme, enterocytes, etc) modifying its oral stability and absorption.   Milli-Q water was added until a volume of 500 mL to finally adjust the pH to 6.8 with 2 M NaOH.
-lis-SIF-panc: lis-SIF supplemented with pancreatin was prepared by dissolving the pancreatin at 1 % w/v in lis-SIF and stirring the mixture for 3 h. Then, the solution was centrifuged (10500 rpm, 10 min) to eliminate pancreatin aggregates. Note that the final pancreatin concentration of 1% is rather an estimated value.
-lis-SIF-muc: lis-SIF supplemented with mucin was prepared by dissolving the mucin at 5 % w/v in in lis-SIF, 3 keeping the mixture under magnetic stirring for 3 h 30 min.
Prior to the analysis, the biological media were kept at 37 °C.