# The Emerging Role of Cyclodextrin Metal-Organic Frameworks in Ostheotherapetics
## 3 Cyclodextrin-Based MOFs
### \(\gamma\)-CD-MOFs Loaded with Anti-Inflammatory Agents for the Management of Osteoarthritis
#### 3.2.1 Preparation and Early Biological Evaluation  
The relatively high aqueous solubility of the components of \(\gamma\)-CD-MOFs makes them susceptible of some degree of disintegration in aqueous media [40]. To avoid this fragility, researchers have sought methods of stabilising the structure of \(\gamma\)-CD-MOFs. The use of a cross-linking agent for the \(\gamma\)-CD molecules affords the desired effect, as it generates an insoluble gel that is able to incorporate water and to have some degree of swelling upon hydration while retaining the cubic shape of the MOF crystallites.  
The first cross-linked \(\gamma\)-CD-MOF-derived material was prepared using the \(\gamma\)-CD-MOF with K\({}^{+}\) as the metal centre as a starting material and ethylene glycol diglycidyl ether as the cross-linking agent (Figure 5) [41].  
\begin{table}
\begin{tabular}{c c c c c} \hline
**Guest Drug** & **Carrier** & \begin{tabular}{c} **In Vivo Studies—GI Tract** \\ **Model** \\ \end{tabular} & **In Vivo Studies** & **Ref.** \\ \hline Diclofenac sodium & Na-\(\gamma\)-CD-MOF & \begin{tabular}{c} Sustained release profile \\ 40\% drug release at 24 h \\ Sustained release profile \\ 40\% drug release at 24 h \\ Sustained release profile \\ 40\% drug release at 24 h \\ Sustained release profile \\ 60\% drug release at 24 h \\ \end{tabular} & \
\begin{tabular}{c} Anti-inflammatory action \\ slightly lower than pure drug \\ Anti-inflammatory action \\ similar to pure drug \\ Three-fold increase in \\ Anti-inflammatory action \\ Two-fold increase of serum \\ half-life (given _per orum_) \\ - \\ - \\ - \\ - \\ \end{tabular} &
\begin{tabular}{c} [38] \\ [38] \\ [38] \\ [38] \\ [38] \\ [38] \\ [38] \\ [39] \\ [40] \\ [41] \\ [42] \\ \end{tabular} \\ \hline \end{tabular}
\end{table}
Table 1: Overview of literature pharmacologic data on NSAID-loaded \(\gamma\)-CD-MOF systems.  
Figure 4: Overview of the non-steroidal anti-inflammatory drugs (NSAIDs) that have been successfully loaded into \(\gamma\)-CD-MOFs.  
In a first step, the \(\gamma\)-CD-MOF was immersed in an ethanol solution of the cross-linking agent and kept for three days at 65 \({}^{\circ}\)C to allow the two epoxy groups to crosslink between the hydroxyl groups of \(\gamma\)-CD molecules. Following, a washing step removed the K\({}^{+}\) ions. The resulting cubic gel particles retained the geometry of \(\gamma\)-CD units from its parent K-\(\gamma\)-CD-MOF [41].  
The safety and biocompatibility of \(\gamma\)-CD-MOF-derived gels has only very recently begun to be explored. The first of these reports, dating from early 2021, described the preparation of gels from crystals of \(\gamma\)-CD-MOF by crosslinking them with diphenyl carbonate. The resulting gel retained the cubic shape of the templating \(\gamma\)-CD-MOF crystals, yielding particles with a mean size of 150 nm. Biodistribution and biocompatibility were evaluated _in vivo_ on C57 BL/6 mice after intravenous administration in the tail vein. Biodistribution, measured 3 h after administration using an _in vivo_ imaging system, showed higher accumulation in the lungs (which led the authors to propose using the cross-linked \(\gamma\)-CD gel as a lung-targeting system). Some accumulation in the liver was observed, and only trace amounts were found in the heart, spleen and kidney. Post-sacrificial histopathologic analysis of mouse heart, liver, spleen and kidney tissue revealed no indicators of normal tissue damage or adverse hematologic effects, thus indicating good biocompatibility [42].