Chemical and biological assessment of metal organic frameworks (MOFs) in pulmonary cells and in an acute in vivo model: relevance to pulmonary arterial hypertension therapy

Abstract

Pulmonary arterial hypertension (PAH) is a progressive and debilitating condition. Despite promoting vasodilation, current drugs have a therapeutic window within which they are limited by systemic side effects. Nanomedicine uses nanoparticles to improve drug delivery and/or reduce side effects. We hypothesize that this approach could be used to deliver PAH drugs avoiding the systemic circulation. Here we report the use of iron metal organic framework (MOF) MIL-89 and PEGylated MIL-89 (MIL-89 PEG) as suitable carriers for PAH drugs. We assessed their effects on viability and inflammatory responses in a wide range of lung cells including endothelial cells grown from blood of donors with/without PAH. Both MOFs conformed to the predicted structures with MIL-89 PEG being more stable at room temperature. At concentrations up to 10 or 30 µg/mL, toxicity was only seen in pulmonary artery smooth muscle cells where both MOFs reduced cell viability and CXCL8 release. In endothelial cells from both control donors and PAH patients, both preparations inhibited the release of CXCL8 and endothelin-1 and in macrophages inhibited inducible nitric oxide synthase activity. Finally, MIL-89 was well-tolerated and accumulated in the rat lungs when given in vivo. Thus, the prototypes MIL-89 and MIL-89 PEG with core capacity suitable to accommodate PAH drugs are relatively non-toxic and may have the added advantage of being anti-inflammatory and reducing the release of endothelin-1. These data are consistent with the idea that these materials may not only be useful as drug carriers in PAH but also offer some therapeutic benefit in their own right.

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

“…PXRD analysis was consistent with literature patterns for bulk MIL-89 (See Figure 1). [2,18,19] Loading and release studies of nanoMIL-89 with sildenafil…”

“…Human blood outgrowth endothelial cells (BOECs) were isolated, cultured, plated, and treated as described previously [2]. Cell viability was indicated by changes in respiration using alamarBlue™ reagent according to manufactures instructions.…”

“…Whilst these drugs show efficacy in PAH, they have limited pharmacokinetics and affect the systemic circulation, which ultimately limits the dose of drug that can be used. As such, we [1][2][3] and others [4][5][6] have suggested that PAH is a disease that would benefit from the application of controlled drug release, with the possibility of introducing targeted drug delivery strategies, using a nanomedicine approach. Whilst this idea is relatively novel, a limited number of studies are emerging describing nanomedicine formulations suitable for application in PAH.…”

“…In this regard, MOFs have several advantages as drug delivery platforms including (i) being biocompatible and biodegradable, (ii) high thermal, chemical and mechanical stability, (iii) control over nanoparticle size, (iv) extremely high porosities with commensurate high drug loading capacity and (v) the ability to tailor the size, shape and chemical nature of the internal and external surfaces thus allowing a high degree of control over drug-binding and release kinetics [11,12]. We have focussed our initial work on the iron-containing MOF, MIL-89 since this particular material has the added advantage of potentially being imageable using magnetic resonance imaging (MRI) [13,14] and a predicted cavity/pore size that is suitable for encapsulating PAH drugs [2]. In our hands, MIL-89 was relatively non-toxic in a range of human cell types, including endothelial and vascular smooth muscle cells and was well tolerated in vivo for two weeks [2].…”

“…We have focussed our initial work on the iron-containing MOF, MIL-89 since this particular material has the added advantage of potentially being imageable using magnetic resonance imaging (MRI) [13,14] and a predicted cavity/pore size that is suitable for encapsulating PAH drugs [2]. In our hands, MIL-89 was relatively non-toxic in a range of human cell types, including endothelial and vascular smooth muscle cells and was well tolerated in vivo for two weeks [2]. In line with this, others have found that a related ironbased MOF was well tolerated in vivo for up to three months [15].…”