Pulmonary arterial hypertension (PAH) is an incurable disease, although symptoms are treated with a range of dilator drugs. Despite their clinical benefits, these drugs are limited by systemic side-effects. It is, therefore, increasingly recognised that using controlled drug-release nanoformulation, with future modifications for targeted drug delivery, may overcome these limitations. This study presents the first evaluation of a promising nanoformulation (highly porous iron-based metal–organic framework (MOF); nanoMIL-89) as a carrier for the PAH-drug sildenafil, which we have previously shown to be relatively non-toxic in vitro and well-tolerated in vivo. In this study, nanoMIL-89 was prepared and charged with a payload of sildenafil (generating Sil@nanoMIL-89). Sildenafil release was measured by Enzyme-Linked Immunosorbent Assay (ELISA), and its effect on cell viability and dilator function in mouse aorta were assessed. Results showed that Sil@nanoMIL-89 released sildenafil over 6 h, followed by a more sustained release over 72 h. Sil@nanoMIL-89 showed no significant toxicity in human blood outgrowth endothelial cells for concentrations up to100µg/ml; however, it reduced the viability of the human pulmonary artery smooth muscle cells (HPASMCs) at concentrations > 3 µg/ml without inducing cellular cytotoxicity. Finally, Sil@nanoMIL-89 induced vasodilation of mouse aorta after a lag phase of 2–4 h. To our knowledge, this study represents the first demonstration of a novel nanoformulation displaying delayed drug release corresponding to vasodilator activity. Further pharmacological assessment of our nanoformulation, including in PAH models, is required and constitutes the subject of ongoing investigations.

Cardiovascular diseases (CVDs) are the leading cause of morbidity and mortality worldwide. Alteration of endothelial cells and the underlying vasculature plays a central role in the pathogenesis of various CVDs. The application of nanoscale materials such as nanoparticles in biomedicine has opened new horizons in the treatment of CVDs. We have previously shown that the iron metal–organic framework nanoparticle, Materials Institut Lavoisier-89 (nanoMIL-89) represents a viable vehicle for future drug delivery of pulmonary arterial hypertension. In this study, we have assessed the cellular uptake of nanoMIL-89 in pulmonary artery endothelial and smooth muscle cells using microscopy imaging techniques. We also tested the cellular responses to nanoMIL-89 using molecular and cellular assays. Microscopic images showed cellular internalization of nanoMIL-89, packaging into endocytic vesicles, and passing to daughter cells during mitosis. Moreover, nanoMIL-89 showed anti-inflammatory activity without any significant cytotoxicity. Our results indicate that nanoMIL-89 formulation may offer promising therapeutic opportunities and set forth a new prototype for drug delivery not only in CVDs, but also for other diseases yet incurable, such as diabetes and cancer.

Footnotes:1 sil@nanoMIL-89; sildenafil loaded nanoMIL-89. AbstractPulmonary 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-89 1 ). 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.

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