Liposomal-delivery of phosphodiesterase 5 inhibitors augments UT-15C-stimulated ATP release from human erythrocytes

Elizabeth A Bowles; Dimitri Feys; Nuran Ercal; Randy S Sprague

doi:10.1016/j.bbrep.2017.09.002

Liposomal-delivery of phosphodiesterase 5 inhibitors augments UT-15C-stimulated ATP release from human erythrocytes

Biochem Biophys Rep. 2017 Sep 12:12:114-119. doi: 10.1016/j.bbrep.2017.09.002. eCollection 2017 Dec.

Authors

Elizabeth A Bowles¹, Dimitri Feys², Nuran Ercal¹, Randy S Sprague³

Affiliations

¹ Department of Chemistry, Missouri University of Science and Technology, 142 Schrenk Hall, 400 W. 11th St., Rolla, MO 65409, USA.
² Department of Civil, Architectural and Environmental Engineering, Missouri University of Science and Technology, 211 Butler-Carlton Hall, 1401 N. Pine St., Rolla, MO 65409, USA.
³ Department of Pharmacological and Physiological Science, Saint Louis University, School of Medicine, 1402 South Grand Blvd., St. Louis, MO 63104, USA.

Abstract

The use of liposomes to affect targeted delivery of pharmaceutical agents to specific sites may result in the reduction of side effects and an increase in drug efficacy. Since liposomes are delivered intravascularly, erythrocytes, which constitute almost half of the volume of blood, are ideal targets for liposomal drug delivery. In vivo, erythrocytes serve not only in the role of oxygen transport but also as participants in the regulation of vascular diameter through the regulated release of the potent vasodilator, adenosine triphosphate (ATP). Unfortunately, erythrocytes of humans with pulmonary arterial hypertension (PAH) do not release ATP in response to the physiological stimulus of exposure to increases in mechanical deformation as would occur when these cells traverse the pulmonary circulation. This defect in erythrocyte physiology has been suggested to contribute to pulmonary hypertension in these individuals. In contrast to deformation, both healthy human and PAH erythrocytes do release ATP in response to incubation with prostacyclin analogs via a well-characterized signaling pathway. Importantly, inhibitors of phosphodiesterase 5 (PDE5) have been shown to significantly increase prostacyclin analog-induced ATP release from human erythrocytes. Here we investigate the hypothesis that targeted delivery of PDE5 inhibitors to human erythrocytes, using a liposomal delivery system, potentiates prostacyclin analog- induced ATP release. The findings are consistent with the hypothesis that directed delivery of this class of drugs to erythrocytes could be a new and important method to augment prostacyclin analog-induced ATP release from these cells. Such an approach could significantly limit side effects of both classes of drugs without compromising their therapeutic effectiveness in diseases such as PAH.

Keywords: ATP, (adenosine triphosphate); DMPC, (1,2-Dimyristoyl-sn-glycero-3-phosphocholine); FSC, (forward scatter); Liposomes; PAH, (pulmonary arterial hypertension); PDE, (phosphodiesterase); PGI2, (prostacyclin); PSS, (physiological salt solution); Red blood cell; SSC, (side scatter); TAD, (tadalafil); Tadalafil; Tadalafil (PubChem CID: 110635); Treprostinil; UT-15C; UT-15C (PubChem CID: 691840); ZAP, (zaprinast),; Zaprinast; Zaprinast (PubChem CID: 5722); cAMP, (cyclic adenosine monophosphate); cGMP, (cyclic guanosine monophosphate); sGC, (soluble guanylyl cyclase).