oa Metal Organic Framework as a Potential Drug Carrier for Pulmonary Arterial Hypertension

Pulmonary arterial hypertension (PAH) is a progressive, debilitating and fatal condition [1]. Current PAH therapy relies on vasodilator drugs, which are seriously limited by their systemic side effects. We suggest that advances made in the field of nanomedicine could be used to improve the utility of drugs to treat PAH. Whilst not currently used clinically, metal organic frameworks (MOFs) such as the Material from Institute Lavoisier (MIL) class, are good candidates since (i) they can be tailored to accommodate different types of drugs including those with the molecular weights of PAH medications (MW; 300-500) [2], (ii) are biocompatible and biodegradable [3]; (iii) have a large internal surface area and low density with commensurate high drug loading capacity; (iv) are thermal and mechanically stable; and (v)have a long drug release period with the ability to incorporate different functional groups [2, 4-6]. However, the idea that nanomedicines can be used to treat PAH is very new and the use of MOFs in this regard is untested. Thus, we must first: (i) validate their chemical structure/stability, (ii) establish MOF cytotoxicity and effect on inflammatory responses in relevant cell types and (iii) investigate their behaviour in vivo model. In PAH, endothelial cells are critical cells to target. This is because the role of endothelial cells in releasing a delicate balance of vasoactive hormones is disrupted in PAH where cardioproective mediators such as nitric oxide and prostacyclin are reduced whilst the release of the constrictor peptide endothelin (ET)-1 is increased. Indeed, current PAH drugs work to boost nitric oxide and prostacyclin pathways and to block ET-1 receptor signalling. Aim: The aims of this work are to (i) synthesis and characterise MOFs designed to accommodate PAH drugs; (ii) to investigate the cytotoxic effect of MOFs in a comprehensive range of cell models relevant to PAH in vitro and the toxicity and distribution of MOFs in vivo. Methods: The nanoporous iron MOF (MIL-89), and a polyethylene glycol formulation (MIL-89 PEG) were prepared as previously described [2], then characterized using infrared spectroscopy (IR), powder X-ray diffraction (PXRD), thermogravimetric analysis (TGA) and scanning electron microscopy (SEM). Endothelial cells grown from human blood progenitors of control subjects and PAH patients were cultured as we have done previously [7] and the effect of MOFs on viability determined using the AlamarBlue® Assay. In addition the effect of MOFs on endothelial cell inflammatory function was determined by measuring the release of the cytokine CXCL8 and on markers of PAH disease by measuring ET-1 using specific ELISAs. To investigate the effects of MOFs in vivo rats were injected with the MOF MIL-89 (50 mg/kg) in glucose solution twice a week for various times up to two weeks, while the control group was injected with glucose solution only. Animals were killed and tissues including; blood, heart, lung, brain, thymus, liver and kidney as well as urine and faeces were collected at days 1,3,7,10 and 14. Results: MIL-89 and MIL-89 PEG retained functional groups, and were crystalline, spherical and stable in air up to 200 °C. Neither preparations caused toxicity in cells grown from control donors or patients with PAH at concentrations up to 10 μg/ml (Fig. 1). Interestingly, both preparations of MOFs displayed anti-inflammatory effects; inhibiting CXCL8 and ET-1 release from endothelial cells from healthy donors as well as from PAH patients (Fig. 1). These MIL-89 had no affect on body weight of the rats and did not cause any gross changes in their lungs (Fig. 2). Conclusion: Both MIL-89 and MIL-89 PEG represent non-toxic potential drug-carriers with predicted molecular capacity for the current PAH medications, which include treprostinil sodium, bosentan and sildenafil. Furthermore, they both display some evidence of anti-inflammatory properties in vitro that may be of therapeutic benefit in the treatment of PAH. MIL-89 had no overt toxic effects in vivo, although these will need to be explored in more detail in future studies.

References

1. Archer, S.L., E.K. Weir, and M.R. Wilkins, Basic science of pulmonary arterial hypertension for clinicians: new concepts and experimental therapies. Circulation, 2010. 121(18): p. 2045-2066.

2. Horcajada, P., et al., Porous metal-organic-framework nanoscale carriers as a potential platform for drug delivery and imaging. Nat Mater, 2010. 9(2): p. 172-178.

3. Huxford, R.C., J. Della Rocca, and W. Lin, Metal-organic frameworks as potential drug carriers. Curr Opin Chem Biol, 2010. 14(2): p. 262-268.

4. Kızılel, S.K.a.S., Biomedical Applications of Metal Organic Framework, 2010, Department of Chemical and Biological Engineering: Koc- University, Rumelifeneri Yolu, 34450, Sarıyer, Istanbul, Turkey.

5. Ferey, G., et al., A chromium terephthalate-based solid with unusually large pore volumes and surface area. Science, 2005. 309(5743): p. 2040-2042.

6. Horcajada, P., et al., Metal-organic frameworks as efficient materials for drug delivery. Angew Chem Int Ed Engl, 2006. 45(36): p. 5974-5978.

7. Reed, D.M., et al., Morphology and vasoactive hormone profiles from endothelial cells derived from stem cells of different sources. Biochem Biophys Res Commun, 2014. 455(3-4): p. 172-177.