Researchers from China developed glucuronic acid (GlcA)-modified liposomes that improved site-specific delivery and bioavailability of treprostinil in a pulmonary arterial hypertension (PAH) rat model.

“This therapeutic platform has the potential to be developed into a generalized approach for PAH management. Future translational studies are warranted,” the authors said in a study published in the European Journal of Pharmacology.

The researchers tested different treprostinil formulations and concluded that treprostinil-loaded GlcA-modified liposomes were the most effective option. This formulation targeted the glucose transporter-1 in pulmonary artery smooth muscle cells, increasing the pulmonary selectivity of treprostinil and improving its effects on relieving PAH symptoms both in vivo and in vitro.


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For instance, treprostinil-loaded GlcA-modified liposomes had a potent inhibitory effect on the remodeling of pulmonary arteries, which has been associated with increased proliferation of pulmonary artery smooth muscle cells. Moreover, they reduced pulmonary arteries medial thickening and collagen deposition, as well as attenuated right ventricle hypertrophy in PAH rats.

These inhibitory effects resulted from the downregulation of growth factors, such as the transforming growth factor-beta 1 and the connective tissue growth factor, which mediate the migration of pulmonary artery smooth muscle cells. In addition, treprostinil promoted the secretion of cyclic adenosine monophosphate and the activation of a downstream signaling pathway that might inhibit the proliferation of pulmonary artery smooth muscle cells.

The researchers found the accumulation of treprostinil to be pulmonary-specific since it inhibited pulmonary arterial pressure but not systemic arterial pressure. The GlcA-modified formulation improved treprostinil bioavailability and sustained its release over time in PAH rats.

The cellular uptake of GlcA-modified liposomes was superior to that of non-GlcA-modified liposomes, regardless of the liposome concentration used. Also, the inhibitory effects of treprostinil on rats’ pulmonary artery smooth muscle cells were enhanced after drug encapsulation in GlcA-modified liposomes.

Reference

Liu A, Li B, Yang M, Shi Y, Su J. Targeted treprostinil delivery inhibits pulmonary arterial remodeling. Eur J Pharmacol. Published online February 5, 2022. doi:10.1016/j.ejphar.2021.174700