A novel vascular homing peptide strategy to selectively enhance pulmonary drug efficacy in pulmonary arterial hypertension

Michie Toba, Abdallah Alzoubi, Kealan O'Neill, Kohtaro Abe, Takeo Urakami, Masanobu Komatsu, Diego Alvarez, Tero A.H. Järvinen, David Mann, Erkki Ruoslahti, Ivan F. McMurtry, Masahiko Oka

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)369-375
Number of pages7
JournalAmerican Journal of Pathology
Volume184
Issue number2
DOIs
StatePublished - Feb 2014

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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    Toba, M., Alzoubi, A., O'Neill, K., Abe, K., Urakami, T., Komatsu, M., Alvarez, D., Järvinen, T. A. H., Mann, D., Ruoslahti, E., McMurtry, I. F., & Oka, M. (2014). A novel vascular homing peptide strategy to selectively enhance pulmonary drug efficacy in pulmonary arterial hypertension. American Journal of Pathology, 184(2), 369-375. https://doi.org/10.1016/j.ajpath.2013.10.008