Departments of Pharmacology and Internal Medicine, Center for Lung Biology, University of South Alabama, College of Medicine, Mobile, Alabama.
Sanford-Burnham Medical Research Institute at Lake Nona, Orlando, Florida.
Am J Pathol. 2014 Feb;184(2):369-75. doi: 10.1016/j.ajpath.2013.10.008. Epub 2014 Jan 6.
A major limitation in the pharmacological treatment of pulmonary arterial hypertension (PAH) is the lack of pulmonary vascular selectivity. Recent studies have identified a tissue-penetrating homing peptide, CARSKNKDC (CAR), which specifically homes to hypertensive pulmonary arteries but not to normal pulmonary vessels or other tissues. Some tissue-penetrating vascular homing peptides have a unique ability to facilitate transport of co-administered drugs into the targeted cells/tissues without requiring physical conjugation of the drug to the peptide (bystander effect). We tested the hypothesis that co-administered CAR would selectively enhance the pulmonary vascular effects of i.v. vasodilators in Sugen5416/hypoxia/normoxia-exposed PAH rats. Systemically administered CAR was predominantly detected in cells of remodeled pulmonary arteries. Intravenously co-administered CAR enhanced pulmonary, but not systemic, effects of the vasodilators, fasudil and imatinib, in PAH rats. CAR increased lung tissue imatinib concentration in isolated PAH lungs without increasing pulmonary vascular permeability. Sublingual CAR was also effective in selectively enhancing the pulmonary vasodilation by imatinib and sildenafil. Our results suggest a new paradigm in the treatment of PAH, using an i.v./sublingual tissue-penetrating homing peptide to selectively augment pulmonary vascular effects of nonselective drugs without the potentially problematic conjugation process. CAR may be particularly useful as an add-on therapy to selectively enhance the pulmonary vascular efficacy of any ongoing drug treatment in patients with PAH.
肺动脉高压（PAH）的药物治疗主要受到缺乏肺血管选择性的限制。最近的研究已经确定了一种组织穿透归巢肽，即 CARSKNKDC（CAR），它可以特异性地靶向高血压性肺血管，而不会靶向正常肺血管或其他组织。一些组织穿透血管归巢肽具有独特的能力，可以促进共给药的药物进入靶向细胞/组织的运输，而不需要药物与肽的物理结合（旁观者效应）。我们测试了以下假设：共给药的 CAR 将选择性增强 Sugen5416/低氧/常氧暴露的 PAH 大鼠中静脉内血管扩张剂的肺血管作用。系统给药的 CAR 主要在重构的肺动脉细胞中被检测到。静脉内共给药的 CAR 增强了 PAH 大鼠的肺血管作用，而不是全身作用，增强了血管扩张剂 fasudil 和 imatinib 的作用。CAR 增加了分离的 PAH 肺组织中的 imatinib 浓度，而不会增加肺血管通透性。舌下 CAR 也可有效选择性增强 imatinib 和西地那非的肺血管舒张作用。我们的结果提出了一种治疗 PAH 的新范例，使用静脉内/舌下组织穿透归巢肽选择性增强非选择性药物的肺血管作用，而无需潜在的有问题的缀合过程。CAR 可能特别有用，可作为附加疗法，选择性增强 PAH 患者任何正在进行的药物治疗的肺血管疗效。
