Biomimetic mesoporous vectors enabling the efficient inhibition of wild-type isocitrate dehydrogenase in multiple myeloma cells

The discovery of isocitrate dehydrogenases (IDHs) mutations in several malignancies has brought to the approval of drugs targeting IDH1/2 mutants in cancers. More recently it has been suggested that the enzymatic inhibition of IDHs may have therapeutic potentials also for wild-type IDH cancers. Specifically, IDH2 inhibition can sensitize multiple myeloma cells to proteasome inhibitors. However, inhibitors directed against native IDHs are not present on the market. Here, we exploited an allosteric inhibitor of mutant IDH2 (AGI-6780), known to also decrease the activity of wild-type IDH2. Since AGI-6780 effectiveness in vivo is limited by its high hydrophobicity and very low bioavailability, the drug was loaded into mesoporous silica nanoparticles (MSNs) with the aim to enhance its efficacy. Furthermore, to enable high drug retention into the silica pores, improve biocompatibility, and reduce the off-target delivery of the drug, a Supported phosphoLipidic Bilayer (SLB) was selfassembled on the outer MSN surface. The silica nanoparticles were thus coated with three different lipid formulations and characterized in terms of structure, size, and morphology. We demonstrated that MSN@SLB nanoparticles have improved colloidal stability and hemocompatibility with respect to pristine MSN. We showed that MSN@SLB formulation displays an excellent loading and retention of the IDH2 inhibitor AGI-6780, with a limited drug leakage depending on the lipid formulation. Finally, we proved that AGI-6780-loaded MSN@SLB nanoparticles efficaciously inhibited the IDH2 enzymatic activity of multiple myeloma cells. Overall, this study provides a proof of concept of drug delivery to multiple myeloma cells by repurposing a neglected/dismissed drug (AGI-6780) with the use of smart nanoparticles and enabling the sensitization of multiple myeloma cells towards other possible treatments.