Targeting Pulmonary Arterial Hypertension

Targeted delivery systems have improved the pharmacokinetic profiles of therapeutics, with increased accumulation of the drug in diseases through the enhanced permeability and retention (EPR) effect. Based on years of extensive experience in delivery system design and development, Creative Biolabs offers high-quality targeted delivery services for pulmonary arterial hypertension (PAH). With the help of our professional scientists, we are confident in providing unique service to meet every customer's requirements.

Pulmonary Arterial Hypertension

PAH is a fatal disease arising from restrained blood flow through pulmonary arterial circulation. The increased flow resistance in PAH induces an overload in the right ventricle (RV), leading to hypertrophy, hyperplasia, and fibrosis. These ultimately result in right heart failure, the major cause of death in PAH patients. Pathophysiologically, PAH attributes to remodeling of the pulmonary vasculature that causes vessel occlusion, muscularization of previously non-muscular vessels, and formation of complex vascular lesions, with pulmonary arteriole smooth muscle cells (PASMCs) and endothelial cells (PAECs) based on the crux of these processes. To date, PAH drug therapies traditionally depend on the regulation of vascular tone, primarily targeting the prostacyclin (PGI2), endothelin (ET), and nitric oxide signaling pathways. Although pharmacotherapies have improved the quality of life, they also expose some disadvantages including short drug half-lives and instability, as well as adverse side effects. Thus, there are no curative treatments currently available for PAH patients save for lung transplantation, emphasizing the importance to develop innovative treatments that can attenuate or even reverse vascular remodeling.

Fig.1 Schematic representation of endothelial dysfunction in PAH and a proposed mechanism of NP extravasation into pulmonary vasculature. (Victor, 2018)

Delivery System Targeting Pulmonary Arterial Hypertension

Nanotechnology-based drug delivery platforms present effective vectors for the packaging of drug and genetic material. Nanoparticles (NPs) consist of either naturally occurring or synthetic, man-made materials. These nano-constructs can be precisely designed according to size and geometry, rendered versatile chemistry enabling tailorability of properties such as enhanced cellular entry and controlled release. For example, a liposomal formulation of fasudil for purposes of aerosolized delivery to lungs undergoing PAH had loading efficiencies >60%, and released ~70% of the drug over the course of 35 h. Pulmonary delivery of liposomes can increase the half-life by more than 10-fold via intratracheal administration, as well as the bioavailability of the drug, compared to a free drug formulation. Liposomal fasudil resulted in a prolonged half-life of vasodilatory effects compared to controls, with a maximal reduction in mPAP of ~40%.

Fig.2 Nanoparticle platforms explored in PAH drug and gene delivery. (Victor, 2018)

In addition, a fasudil liposomes with the peptide CARSKNKDC has been developed, which recognizes cell surface heparan sulfate found overexpressed in pulmonary vasculature in PAH. In this system, liposomes showed a sustained release of fasudil over the course of 120 h. Peptide-coated liposomes produce ~ 34- fold increase in the half-life of the drug compared to an IV administered formulation of free drug. Recently, superoxide dismutase (SOD) was incorporated into their peptide-targeted fasudil liposomes, with the hypothesis that inclusion of a reactive oxygen species (ROS) scavenger would further enhance efficacy, given the role that increased ROS levels play in vascular remodeling in PAH. In an MCT-model of PAH, the duration of vasodilatory effects was significantly increased in rats receiving targeted liposomes containing both fasudil and SOD compared to free drug controls. In a Sugen/Hypoxia model of PAH, mPAP was significantly reduced in rats receiving targeted liposomes containing both fasudil and SOD compared to free drug controls.

What Can We Do for You?

Nanoparticles have been used widely as a novel drug delivery system. Drug-incorporated nanoparticles for local delivery might optimize the efficacy and minimize the side effects of drugs. Creative Biolabs is a leading service provider in targeted delivery,  and we has built some advanced module delivery systems. We can provide custom-specific raw materials and products for delivery system construction. Moreover, we offer a wide range of customized targeted delivery services to meet our clients' unique requirements. Please do not hesitate to contact us for more details.

Reference

1. Victor, S. I.; et al. Nanotherapeutics for treatment of pulmonary arterial hypertension. Frontiers in Physiology. 2018, 9, 890.

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