title: A novel vascular homing peptide strategy to selectively enhance pulmonary drug efficacy in pulmonary arterial hypertension.
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.
authors.affiliation: Departments of Pharmacology and Internal Medicine, Center for Lung Biology, University of South Alabama, College of Medicine, Mobile, Alabama.
authors.forename: Michie
authors.initials: M
authors.lastname: Toba
authors.affiliation: Departments of Pharmacology and Internal Medicine, Center for Lung Biology, University of South Alabama, College of Medicine, Mobile, Alabama.
authors.forename: Abdallah
authors.initials: A
authors.lastname: Alzoubi
authors.affiliation: Departments of Pharmacology and Internal Medicine, Center for Lung Biology, University of South Alabama, College of Medicine, Mobile, Alabama.
authors.forename: Kealan
authors.initials: K
authors.lastname: O'Neill
authors.affiliation: Departments of Pharmacology and Internal Medicine, Center for Lung Biology, University of South Alabama, College of Medicine, Mobile, Alabama.
authors.forename: Kohtaro
authors.initials: K
authors.lastname: Abe
authors.affiliation: Sanford-Burnham Medical Research Institute at Lake Nona, Orlando, Florida.
authors.forename: Takeo
authors.initials: T
authors.lastname: Urakami
authors.affiliation: Sanford-Burnham Medical Research Institute at Lake Nona, Orlando, Florida.
authors.forename: Masanobu
authors.initials: M
authors.lastname: Komatsu
authors.affiliation: Departments of Pharmacology and Internal Medicine, Center for Lung Biology, University of South Alabama, College of Medicine, Mobile, Alabama.
authors.forename: Diego
authors.initials: D
authors.lastname: Alvarez
authors.affiliation: Medical School, University and University Hospital of Tampere, Tampere, Finland.
authors.forename: Tero A H
authors.initials: TA
authors.lastname: Järvinen
authors.affiliation: VBS Pharmaceuticals Division, Vascular BioSciences, Goleta, California.
authors.forename: David
authors.initials: D
authors.lastname: Mann
authors.affiliation: Cancer Center, Sanford-Burnham Medical Research Institute, La Jolla, California.
authors.forename: Erkki
authors.initials: E
authors.lastname: Ruoslahti
authors.affiliation: Departments of Pharmacology and Internal Medicine, Center for Lung Biology, University of South Alabama, College of Medicine, Mobile, Alabama.
authors.forename: Ivan F
authors.initials: IF
authors.lastname: McMurtry
authors.affiliation: Departments of Pharmacology and Internal Medicine, Center for Lung Biology, University of South Alabama, College of Medicine, Mobile, Alabama. Electronic address: moka@usouthal.edu.
authors.forename: Masahiko
authors.initials: M
authors.lastname: Oka
mesh_terms: D000286:Administration, Sublingual; D000595:Amino Acid Sequence; D000818:Animals; D001157:Arterial Occlusive Diseases / Q000188:drug therapy / Q000473:pathology; D001549:Benzamides / Q000494:pharmacology / Q000627:therapeutic use; D016503:Drug Delivery Systems / Q000379:methods*; D065627:Familial Primary Pulmonary Hypertension; D006439:Hemodynamics / Q000187:drug effects; D006976:Hypertension, Pulmonary / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D000068877:Imatinib Mesylate; D007262:Infusions, Intravenous; D007275:Injections, Intravenous; D008297:Male; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry*; D010879:Piperazines / Q000494:pharmacology / Q000627:therapeutic use; D011651:Pulmonary Artery / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D016896:Treatment Outcome; D014665:Vasodilator Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D001549:Benzamides; D010455:Peptides; D010879:Piperazines; D011743:Pyrimidines; D014665:Vasodilator Agents; D000068877:Imatinib Mesylate