Studies on metal–organic framework (MOF) nanomedicine preparations of sildenafil for the future treatment of pulmonary arterial hypertension

• Published in: Scientific reports Vol. 11; no. 1; pp. 4336 - 8
• Main Authors: Mohamed, Nura A., Abou-Saleh, Haissam, Kameno, Yu, Marei, Isra, de Nucci, Gilberto, Ahmetaj-Shala, Blerina, Shala, Fisnik, Kirkby, Nicholas S., Jennings, Lewis, Al-Ansari, Dana E., Davies, Robert P., Lickiss, Paul D., Mitchell, Jane A.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 22-02-2021; Nature Publishing Group; Nature Portfolio
• Subjects: 639/925; 639/925/352; 639/925/352/152; Animals; Aorta; Aorta - drug effects; Cell Survival - drug effects; Cell viability; Controlled release; Coronary vessels; Cytotoxicity; Drug delivery; Drug Liberation; Endothelial cells; Enzyme-linked immunosorbent assay; Humanities and Social Sciences; Humans; Hypertension; Kinetics; Lag phase; Metal-Organic Frameworks - chemistry; Metal-Organic Frameworks - ultrastructure; Mice; multidisciplinary; Myocytes, Smooth Muscle - drug effects; Myocytes, Smooth Muscle - metabolism; Nanotechnology; Phosphodiesterase 5 Inhibitors - administration & dosage; Phosphodiesterase 5 Inhibitors - chemistry; Phosphodiesterase 5 Inhibitors - pharmacokinetics; Pulmonary Arterial Hypertension - drug therapy; Pulmonary Arterial Hypertension - etiology; Pulmonary arteries; Pulmonary artery; Pulmonary hypertension; Science; Science (multidisciplinary); Side effects; Sildenafil; Sildenafil Citrate - administration & dosage; Sildenafil Citrate - chemistry; Sildenafil Citrate - pharmacokinetics; Smooth muscle; Spectrum Analysis; Theranostic Nanomedicine; Vasodilation; Vasodilator Agents - administration & dosage; Vasodilator Agents - chemistry; Vasodilator Agents - pharmacokinetics
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-021-83423-6

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.