(193n) Therapeutic Effect of Inhaled Tacrolimus-Loaded Nanocomposite Microparticles (nCmP) in a Pulmonary Hypertension Induced Rat Model

Pulmonary arterial hypertension (PAH) is a progressive cardiovascular disease, which hemo-dynamically is defined as an increased mean pulmonary arterial pressure higher than 25 mmHg at rest and 30 mmHg with exercise. Pulmonary drug delivery options have attracted increasing attention recently as they are capable of delivering therapeutics directly and efficiently to the lungs. As the result, pulmonary delivery systems exhibit advantages including increased local drug concentration, reduced side effects, rapid onset of action due to the enormous surface area and plentiful capillary vessels in the lung, and avoidance of the first-pass metabolism of the liver. Tacrolimus (TAC) is an immunosuppressant recently found to be useful in treating PAH as it reverses the BMPR-2 mutation associated with certain types of PAH. This study aimed to formulate TAC-loaded nanocomposite microparticles (nCmP) and investigate the therapeutic effect of inhaled TAC for the treatment of pulmonary hypertension in a rat model.

Acetalated dextran (Ac-Dex) is an acid-sensitive, biodegradable, and biocompatible polymer prepared in a one-step reaction by reversibly modifying hydrophilic dextran to acetalated dextran with hydrophobic groups. As compared to other commonly used polymers such as poly (lactic-co-glycolic acid) (PLGA), polylactic acid (PLA), and poly-ϵ-caprolactone (PCL), Ac-Dex exhibits attractive properties suitable for the controlled release of therapeutic payloads. By controlling the reaction time during the formation of Ac-Dex, the ratio of cyclic acetal groups with a slower degradation rate to acyclic acetal groups with a faster degradation rate can be tuned. Moreover, the acid-sensitivity of Ac-Dex enables it to degrade faster in lower pH environments such as the lysosomes of macrophages or tumor cells, resulting in faster release of drug in such environments, while controlling the release before reaching them. Furthermore, Ac-Dex degrades into neutral by-products, which avoids undesirable changes of the micro-environmental pH in the body. Therefore, Ac-Dex was used to form nanoparticles (NP) loaded with TAC via a emulsion/solvent evaporation method followed by spray drying to form dry powder nCmP.

To induce PAH, adult Sprague-Dawley rats weighing 150–175 g were placed into a normobaric hypoxia chamber (10% FiO₂; Biospherix Ltd., Parish, NY) or room air for three weeks. A DP-4M insufflator (Penn-Century Inc., Philadelphia, PA) was used to administer the TAC-loaded nCmP into PAH-induced rat lungs. The pharmacokinetics and pharmacodynamics properties were assessed after the TAC nCmP were administered to the rats. In addition, the efficacy of the nCmP formulation towards the treatment of PAH was evaluated.

Keywords: Pulmonary hypertension; Tacrolimus; Acetalated dextran; Nanoparticles; Microparticle