Fenestrated vasculature from ongoing angiogenesis contributes immensely to the heightened accumulation of NPs in tumors, through a phenomenon known as the enhanced permeability and retention (EPR) effect. Importantly, this characteristic of tumor vasculature is present in other diseases. Hearts undergoing heart failure have endothelial dysfunction. We demonstrated particle accumulation in a murine model of preclinical heart failure (Eur J Heart Fail, 2016, 18, 2). Particles accumulated to a greater extent in failing hearts compared to normal hearts after intravenous (IV) administration.
We hypothesized that a similar phenomenon would occur in lungs exhibiting pulmonary arterial hypertension (PAH). Endothelial remodeling in pulmonary arterial hypertension (PAH) can induce vascular fenestrations, which were expected to facilitate NP extravasation and accumulation through disrupted endothelium. We demonstrated heightened accumulation of NPs administered systemically (IV) in a preclinical model of PAH (Int J Pharm, 2017, 524, 1-2). We examined the efficacy of NPs containing rapamycin (RAP), an mTOR inhibitor, in a monocrotaline (MCT)-induced rat model of PAH. When compared to free RAP, RAP NPs led to a much greater increase in RAP concentration in lungs from MCT-exposed rats. RAP NPs prevented PAH, displaying a marked improvement over non-treated controls.
Nanoparticle-based drug and gene delivery remains an active area of research in the laboratory, with various projects focused on pulmonary delivery for chronic lung diseases such as PAH and idiopathic pulmonary fibrosis (IPF), as well as heart failure.