Metal-organic framework (MOF) nanomedicine preparations of sildenafil designed for the future treatment of pulmonary arterial hypertension

Abstract

Pulmonary Arterial Hypertension (PAH) is an aggressive disease with poor prognosis, no available cure, and low survival rates. Currently, there are several classes of vasodilator drugs that are widely used as treatment strategies for PAH. These include (i) endothelin-1 receptor antagonists, (ii) phosphodiesterase type 5 inhibitors, (iii) prostacyclin analogues, and (iv) soluble guanylate cyclase activators. Despite their clinical benefits, these therapies are hindered by their systemic side effects. This limitation could be overcome by controlled drug release, with future modifications for targeted drug delivery, using a nanomedicine approach. In the current study, we have evaluated one particular nanomedicine platform (the highly porous iron-based metal-organic framework (MOF) commonly referred to as MIL-89) as a carrier of the PAH drug sildenafil. We have previously shown that MIL-89 is relatively non-toxic in a range of human cell types and well tolerated in vivo. Here we prepared a nano-formulation of MIL-89 (nanoMIL-89) and then successfully charged it with a payload of sildenafil (sil@nanoMIL-891). sil@nanoMIL-89 was then shown to release sildenafil in a biphasic manner with an initial rapid release over 6 hours followed by a more sustained release over 72 hours. Both nanoMIL-89 and sil@nanoMIL-89 were relatively non-toxic when incubated with human endothelial cells for 24 hours. Finally, the vasodilator effect of sil@nanoMIL-89 was measured over 8 hours using isolated mouse aorta. Consistent with drug release kinetics, sil@nanoMIL-89 induced vasodilation after a lag phase of >4 hours. Thus, in sil@nanoMIL-89, we have produced a nano-formulation of sildenafil displaying delayed drug release corresponding to vasodilator activity. Further pharmacological assessment of sil@nanoMIL-89, including in PAH models, is now required and constitutes the subject of ongoing investigation.