# The Emerging Role of Cyclodextrin Metal-Organic Frameworks in Ostheotherapetics
## 2 Cyclodextrin-Coated Metal-Organic Frameworks of the MIL Series  
The MIL series (where MIL is the acronym for Materiaux de l'Institut Lavoisier) comprises iron-based porous materials with carboxylic acids as the ligands. There are several families within the MIL series, with the MIL-88 being characterised by the presence of a hexagonal unit cell in their structures, and by having the general formula [Fe\({}_{3}\)(O-L-)\({}_{3}\)]\({}_{2}\), where the ligand (L) is fumaric acid in MIL-88A and 1,4-benzenedicarboxylic acid in MIL-88B (Figure 1) [27; 28].  
MIL-88A is fully biocompatible as it is composed of an organic acid that exists in the organism (being part of the Krebs cycle). Degradation to release the components of the  
Figure 1: Structural representation of MIL-88A (_left_) and MIL-88B (_right_), with carbon atoms represented in grey, oxygen atoms in red and iron atoms in orange; solvent molecules are omitted for clarity. Drawn with the software Mercury 3.5.1 (Copyright CCDC 2001–2014) from the atomic coordinates of MIL-88A (refcode FAVKAP) and of MIL-88B (refcode HAMXIG), available at the Cambridge Structural Database.  
MOF is the natural fate of bioMOFs; this way, MIL-88A degrades into its components under physiological conditions, releasing fumaric acid and iron [29].  
Functionalisation of the surface of MOF particles with adequate organic molecules can contribute to fine-tune their properties or even to bring new biological functionalities. Functionalisation is useful to control the release of APIs carried inside the MOFs because it can reduce the size of the pores at the surface and, thus, limit diffusion to the external medium. Early steps in the functionalisation of MOFs with cyclodext were conducted on MIL-100, which is based on the ligand 1,3,5-benzenetricarboxilic acid [30]. Using phosphate derivatives of \(\beta\)-CD, it was possible to coat nanoparticles of MIL-100 in mild conditions (_i.e._, stirring in an aqueous medium at ambient temperature). The phosphate groups of the \(\beta\)-CD derivative coordinated with the available FeIII sites at the surface of MIL-100 crystallites without penetrating inside the MOF because they were too bulky to enter its pores. Coating the MOF with phosphate-\(\beta\)-CD was shown to help in stabilising it as a colloidal suspension in aqueous media without affecting the release rate of the API. Furthermore, \(\beta\)-CD-coated MIL-100 showed no _in vitro_ cytotoxic effect on macrophages of the J774 cell line, which was interpreted as indicative of adequate biocompatibility.  
Coating MIL-88B with \(\beta\)-CD followed a different approach. MIL-88B was prepared with a modified ligand having a free amine group, affording MIL-88B-NH\({}_{2}\). This material was suspended in DMF and allowed to react with toyslated \(\beta\)-CD in the presence of trimethylamine (all in anhydrous conditions and under inert atmosphere) [31]. Following, \(\beta\)-CD-coated MIL-88B was loaded with alendronate, one of the most commonly prescribed bisphosphonates for osteoporosis, and evaluated regarding the API release profile. Results showed an initial burst effect, which was attributed to the release of alendronate loaded at the surface of the MOF, followed by a slow and sustained diffusion-controlled release, corresponding to the molecules of alendronate carried inside the pores of the MOF. Notably, the sustained release profile was observed for as long as 28 days (the total time of observation in the study).