Abstract 2306: An Innovative Therapeutic Approach for Pulmonary Arterial Hypertension: Single Intratracheal Administration of Bioabsorbable Nanoparticle Incorporated with Statin Ameliorates Monocrotaline-induced Pulmonary Artery Hypertension and Survival
Background: Pulmonary arterial hypertension (PAH) is a life-threatening disease (5-year survival remains at 50 %) with few satisfactory therapeutic options. Multiple vasculoprotective actions of HMG-CoA reductase inhibitors (statin) may ameliorate experimental PAH, however, optimal nanotechnology-based drug delivery system (Nano-DDS) to the lung is needed for translation to clinical application. We have developed such Nano-DDS using bioabsorbable polymeric PLGA nanoparticle (NP, a mean diameter of 50 nm) for intratracheal delivery.
Hypothesis: Intratracheal delivery of NP encapsulated with statin ameliorates monocrotaline (MCT)-induced PAH and survival.
Methods and Results: [Prevention protocol] Single intratracheal injection of fluorescence marker incorporated NPs in rats resulted in sustained intracellular delivery into macrophages and small bronchial system until 7–14 days. After MCT injection, rats were randomly divided into no treatment (No Tx) group, and those received intratracheal pitavastatin alone (100 μg), blank NP alone, or NPs containing 100 μg of pitavastatin (n=6, each). No Tx group developed significant PAH, remodeling of pulmonary arteries, and increased infiltration of macrophages 3 weeks after MCT injection. These pathologic changes were ameliorated by treatment with statin NPs, but not with statin only or blank NP only. [Treatment protocol] The Nano-DDS of statin was started 3 weeks after MCT injection when severe PAH is established. Kaplan-Meier survival analysis demonstrated better survival rate by statin NP group (survival rate: 69 versus 34 % at 14 days, p<0.05).
Conclusions: Nano-DDS of statin to the lung with bioabsorbable polymeric NP demonstrated the therapeutic benefit associated with decreased inflammation in MCT-induced PAH model. This study provides an innovative future direction of less invasive and dependable Nano-DDS for patients with severe PAH.