Assessment of nanomedicine preparations as potential therapies for pulmonary arterial hypertension

Abstract

Pulmonary arterial hypertension (PAH) is an aggressive disease with poor prognosis, no available cure and with survival rates of 2-5 years after diagnosis. However, there are drugs available, which work by enhancing dilator pathways or blocking constrictors that limit progression of the disease; Unfortunately these drugs have the critical limitation of dilator effects in the systemic circulation and are associated with class specific side effects. One way of overcoming systemic (and other) side effects is to employ a nanomedicine approach where drugs can be encapsulated in a nano-sized (≈100nm) carrier molecule and directed specially to the diseased vessels of the lung. Nanoparticles used in the medical field are classified to being organic or inorganic. In my PhD I investigated the effects of two nanomedicine formulations in biological systems one organic and one inorganic. Firstly I prepared an iron (Fe) containing metal organic framework (MOF), MIL-89 and it is PEGylated form (MIL-89 PEG).. MIL-89 preparations confirmed to the predicted structure and were non-toxic in vitro and in vivo with some potential anti-inflammatory effects at high concentrations. Unfortunately loading MIL-89 with drug and assessing effects in relevant systems was beyond the scope of my PhD thesis, but future development of MIL-89 in a PAH setting is discussed throughout. Secondly I studied the chemical and biological effects of a novel NO-releasing nanomedicine formulation consisting of nitrated polymers (NO-NP). NO-NP released NO, is relatively non-toxic, inhibited some aspects of inflammation and was an effective vasodilator with selectively towards pulmonary artery over systemic vessels (aorta). The data in my thesis are consistent with the idea that a nanomedicine approach is achievable in PAH and my personal view is that in the future PAH drugs will be delivered as targeted therapies with the potential of converting PAH into a chronic drug-managed condition.