Bowles Elizabeth A, Feys Dimitri, Ercal Nuran, Sprague Randy S
Department of Chemistry, Missouri University of Science and Technology, 142 Schrenk Hall, 400 W. 11th St., Rolla, MO 65409, USA.
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.
Biochem Biophys Rep. 2017 Sep 12;12:114-119. doi: 10.1016/j.bbrep.2017.09.002. eCollection 2017 Dec.
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.
使用脂质体来实现药物向特定部位的靶向递送可能会减少副作用并提高药物疗效。由于脂质体是通过血管内给药，而红细胞几乎占血液体积的一半，因此红细胞是脂质体药物递送的理想靶点。在体内，红细胞不仅起着运输氧气的作用，还通过调节释放强效血管舒张剂三磷酸腺苷（ATP）参与血管直径的调节。不幸的是，患有肺动脉高压（PAH）的人的红细胞不会像这些细胞在肺循环中穿行时那样，对机械变形增加的生理刺激做出反应而释放ATP。有人认为红细胞生理功能的这种缺陷导致了这些个体的肺动脉高压。与变形不同，健康人的红细胞和PAH患者的红细胞在与前列环素类似物孵育时，都会通过一条特征明确的信号通路释放ATP。重要的是，磷酸二酯酶5（PDE5）抑制剂已被证明能显著增加前列环素类似物诱导的人红细胞ATP释放。在此，我们研究了一个假说，即使用脂质体递送系统将PDE5抑制剂靶向递送至人红细胞，可增强前列环素类似物诱导的ATP释放。这些发现与以下假说一致，即这类药物向红细胞的定向递送可能是一种新的重要方法，可增强前列环素类似物诱导的这些细胞的ATP释放。这种方法可以在不影响其在PAH等疾病中的治疗效果的情况下，显著限制这两类药物的副作用。
