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

2019 ◽  
Author(s):  
Nura A. Mohamed ◽  
Haissam Abou Saleh ◽  
Yu Kameno ◽  
Isra Marei ◽  
Gilberto de Nucci ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Drug Release ◽  
Arterial Hypertension ◽  
Metal Organic Framework ◽  
Porous Iron ◽  
Phosphodiesterase Type 5 Inhibitors ◽  
Metal Organic ◽  
Pulmonary Arterial ◽  
Nano Formulation ◽  
Organic Framework

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-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.

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

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Nura A. Mohamed ◽  
Haissam Abou-Saleh ◽  
Yu Kameno ◽  
Isra Marei ◽  
Gilberto de Nucci ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Drug Release ◽  
Arterial Hypertension ◽  
Metal Organic Framework ◽  
Enzyme Linked Immunosorbent Assay ◽  
Porous Iron ◽  
Metal Organic ◽  
Pulmonary Arterial ◽  
Mouse Aorta ◽  
Organic Framework

AbstractPulmonary 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.

scholarly journals Replacing a phosphodiesterase-5 inhibitor with riociguat in patients with connective tissue disease-associated pulmonary arterial hypertension: a case series

2017 ◽  
Vol 7 (3) ◽  
pp. 741-746 ◽  
Author(s):  
Amresh Raina ◽  
Raymond L. Benza ◽  
Harrison W. Farber
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Connective Tissue ◽  
Arterial Hypertension ◽  
Clinical Response ◽  
Connective Tissue Disease ◽  
Case Series ◽  
Response To Treatment ◽  
Tolerability Profile ◽  
Phosphodiesterase Type 5 Inhibitors ◽  
Pulmonary Arterial

Patients with pulmonary arterial hypertension associated with connective tissue disease (PAH-PAH-CTD) such as systemic sclerosis (SSc) have a poorer response to treatment and increased mortality compared with patients with idiopathic PAH. Current treatment options for PAH-CTD include prostanoids, phosphodiesterase type-5 inhibitors (PDE-5i), endothelin receptor antagonists, and the soluble guanylate cyclase stimulator riociguat. In this case series, we describe three patients with PAH-CTD related to limited scleroderma who were switched from a PDE-5i to riociguat due to insufficient clinical response. The switch to riociguat was associated with an improvement in respiratory and hemodynamic parameters and a favorable tolerability profile. These cases demonstrate that switching to riociguat is a therapeutic option in patients with PAH-CTD who have not achieved a satisfactory clinical response to a PDE-5i.

scholarly journals Mechanochemical Approaches Towards the in Situ Confinement of 5-FU Anti-Cancer Drug Within MIL-100 (Fe) Metal-Organic Framework

2020 ◽  
Author(s):  
Barbara Souza ◽  
Jin-Chong Tan
Keyword(s):  
Drug Release ◽  
Metal Organic Framework ◽  
Cancer Drug ◽  
One Pot ◽  
Host Interactions ◽  
Anti Cancer ◽  
Metal Organic ◽  
Iron Based ◽  
Organic Framework

We report two solvent-free mechanochemical methods to achieve one‑pot encapsulation of anti-cancer drug 5‑Fluorouracil (5‑FU) in the iron-based MIL‑100 metal-organic framework (MOF). We compare the structural and physicochemical properties of drug@MIL‑100 systems derived from <i>in situ </i>manual and vortex grinding, where the former exhibits a slower drug release due to stronger guest-host interactions.

A Bayesian Network Meta-analysis of Add-on Drug Therapies Specific for Pulmonary Arterial Hypertension

2019 ◽  
Vol 54 (5) ◽  
pp. 423-433 ◽  
Author(s):  
Maja Petrovič ◽  
Igor Locatelli
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Combination Therapy ◽  
Arterial Hypertension ◽  
Meta Analysis ◽  
Phosphodiesterase Type 5 Inhibitors ◽  
Number Of Patients ◽  
All Cause Mortality ◽  
Pulmonary Arterial ◽  
Meta Analyses ◽  
Better Than

Background: Recently published meta-analyses did not discriminate between drug agents used for initial and sequential combination therapy. Objective: To assess the comparative efficacy of drugs specific for the treatment of pulmonary arterial hypertension (PAH) as add-on therapies based on 6-minute walk distance (6MWD), all-cause mortality, and discontinuation due to adverse events (AEs). Methods: EMBASE, PubMed, Cochrane Library, and ClinicalTrials.gov were searched until December 9, 2018, for the randomized, placebo-controlled clinical trials (RCTs) conducted on primarily adult patients diagnosed with PAH. Data extracted from applicable RCTs were as follows: for 6MWD mean change from baseline, the total number of patients, and the number of patients with events, per treatment. Network meta-analysis (NMA) was conducted in a Bayesian framework. Results: A total of 16 RCTs were eligible for analysis, with 4112 patients. Add-on therapy with tadalafil or inhaled treprostinil performed better than endothelin receptor antagonists alone [27 m; 95% credible interval (CrI): (11, 43); and 19 m; 95% CrI: (10, 27); respectively]. Add-on therapy with macitentan or bosentan performed better than phosphodiesterase type 5 inhibitors alone [26 m; 95% CrI: (6.4, 45); and 22 m; 95% CrI: (5.1, 38); respectively]. Differences in all-cause mortality and discontinuation due to AEs were nonsignificant. Conclusion and Relevance: Our NMA evaluated efficacy and safety of add-on therapies in patients with PAH. None of the previous meta-analyses evaluated RCTs focusing solely on patients pretreated with another PAH-specific drug therapy. Our results support guideline recommendations on combination therapy in PAH patients and add the quantitative perspective on which sequential therapy demonstrated the greatest effect size.

scholarly journals In Vitro Toxicity Study of a Porous Iron(III) Metal‒Organic Framework

Molecules ◽  
2019 ◽  
Vol 24 (7) ◽  
pp. 1211 ◽  
Author(s):  
Gongsen Chen ◽  
Xin Leng ◽  
Juyuan Luo ◽  
Longtai You ◽  
Changhai Qu ◽  
...  
Keyword(s):  
Metal Organic Framework ◽  
Drug Carrier ◽  
In Vitro Cytotoxicity ◽  
In Vitro Toxicity ◽  
Porous Iron ◽  
Dapi Staining ◽  
Toxicological Assessment ◽  
Metal Organic ◽  
Organic Framework

A MIL series metal‒organic framework (MOF), MIL-100(Fe), was successfully synthesized at the nanoscale and fully characterized by TEM, TGA, XRD, FTIR, DLS, and BET. A toxicological assessment was performed using two different cell lines: human normal liver cells (HL-7702) and hepatocellular carcinoma (HepG2). In vitro cytotoxicity of MIL-100(Fe) was evaluated by the MTT assay, LDH releasing rate assay, DAPI staining, and annexin V/PI double staining assay. The safe dose of MIL-100(Fe) was 80 μg/mL. It exhibited good biocompatibility, low cytotoxicity, and high cell survival rate (HL-7702 cells’ viability >85.97%, HepG2 cells’ viability >91.20%). Therefore, MIL-100(Fe) has a potential application as a drug carrier.

Sign in / Sign up

Export Citation Format

Share Document