Porous drug-loaded nanoparticles with engineered coatings

The use of nanoscale metal organic frameworks (nanoMOFs) in diagnosis and treatment of severe diseases such as cancer and infections is of increasing interest. Nonetheless, immediately after their administration, nanoMOFs strongly interact with their physiological environment, including plasma proteins and cells. As a result, they are rapidly cleared from the blood circulation and cannot reach their targets. This premature elimination significantly limits the nanoMOF use in clinical practice.
To address the challenges related to the nanoMOF sequestration by the immune system, we developed two strategies to cover the nanoMOFs with “stealth” coatings. To do so, poly(ethylene glycol) (PEG) chains were covalently grafted to polymers which were adsorbed onto the nanoMOFs.
Compared to dense non porous nanoparticles, the surface modification of porous nanoMOFs is much more challenging. Indeed, it was disclosed that PEG chains can penetrate into the pores, displacing the loaded drug. Therefore, in this study, we developed different strategies to modify the surface of nanoMOF particles with multi-functional coatings without disturbing their drug loading capacity.
The first strategy was to synthesize comb-like co-polymers made of of dextran (DEX), PEG and alendronate (ALN). DEX acts as bulky macromolecule preventing the PEG chains to penetrate inside the nanoMOFs, whereas ALN moieties are the iron complexing groups to firmly anchor the coatings to the nanoMOFs. The DEX-ALN-PEG copolymers were obtained by click chemistry. They were spontaneously coated onto the nanoMOFs by incubation in water.
The resulting stable shells successfully decreased the nanoMOFs’ uptake by macrophages in vitro.
In an alternative approach, biodegradable PEG-based coatings were engineered by cross-linking PEG-grafted γ-cyclodextrin (CD) with citric acid, which could also efficiently coordinate with nanoMOF surface iron sites. In addition, the CD cavities offer additional benefits such as drug incorporation inside the shell. The copolymers could be functionalized also with fluorophores such as Cyanines-5, allowing deciphering the coating mechanism. Doxorubicin (DOX) was successfully incorporated into the core-shell nanoMOFs reaching loadings up to 64±2 wt%. According to solid state nuclear magnetic resonance (ssNMR) investigations, DOX located both in the cores and in the shells.
Remarkably, the incorporated DOX didn’t release out at physiological pH 7.4, whereas it released out immediately in artificial lysosome fluid (ALF). Confocal microscopy investigations were in good agreement with these findings : when nanoMOFs were put in contact with cancer cells (Hela cell line), DOX was not released in the extracellular medium, but only inside the cells. Noteworthy, the engineered nanoMOFs penetrate inside the cells together with their coatings, and then degrade intracellularly, releasing both their coatings and the active dug cargo, which in turn eradicated the cancer cells.
This study pave the way towards engineered the surface of highly porous particles for biomedical applications.