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

TitleA novel vascular homing peptide strategy to selectively enhance pulmonary drug efficacy in pulmonary arterial hypertension.
Publication TypeJournal Article
Year of Publication2014
AuthorsToba M, Alzoubi A, O'Neill K, Abe K, Urakami T, Komatsu M, Alvarez D, Järvinen TAH, Mann D, Ruoslahti E, McMurtry IF, Oka M
JournalAm J Pathol
Volume184
Issue2
Pagination369-75
Date Published2014 Feb
ISSN1525-2191
KeywordsAdministration, Sublingual, Amino Acid Sequence, Animals, Arterial Occlusive Diseases, Benzamides, Drug Delivery Systems, Familial Primary Pulmonary Hypertension, Hemodynamics, Hypertension, Pulmonary, Infusions, Intravenous, Injections, Intravenous, Male, Molecular Sequence Data, Peptides, Piperazines, Pulmonary Artery, Pyrimidines, Rats, Rats, Sprague-Dawley, Treatment Outcome, Vasodilator Agents
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.

DOI10.1016/j.ajpath.2013.10.008
Alternate JournalAm. J. Pathol.
PubMed ID24401613
PubMed Central IDPMC3906494
Grant ListCA125255 / CA / NCI NIH HHS / United States
CA152327 / CA / NCI NIH HHS / United States
HL106101 / HL / NHLBI NIH HHS / United States
P01 HL066299 / HL / NHLBI NIH HHS / United States
R01 CA152327 / CA / NCI NIH HHS / United States