title: Peptide-directed highly selective targeting of pulmonary arterial hypertension.
abstract: Pulmonary arterial hypertension (PAH) is a disorder of the pulmonary vasculature associated with elevated pulmonary vascular resistance. Despite recent advances in the treatment of PAH, with eight approved clinical therapies and additional therapies undergoing clinical trials, PAH remains a serious life-threatening condition. The lack of pulmonary vascular selectivity and associated systemic adverse effects of these therapies remain the main obstacles to successful treatment. Peptide-mediated drug delivery that specifically targets the vasculature of PAH lungs may offer a solution to the lack of drug selectivity. Herein, we show highly selective targeting of rat PAH lesions by a novel cyclic peptide, CARSKNKDC (CAR). Intravenous administration of CAR peptide resulted in intense accumulation of the peptide in monocrotaline-induced and SU5416/hypoxia-induced hypertensive lungs but not in healthy lungs or other organs of PAH rats. CAR homed to all layers of remodeled pulmonary arteries, ie, endothelium, neointima, medial smooth muscle, and adventitia, in the hypertensive lungs. CAR also homed to capillary vessels and accumulated in the interstitial space of the PAH lungs, manifesting its extravasation activity. These results demonstrated the remarkable ability of CAR to selectively target PAH lung vasculature and effectively penetrate and spread throughout the diseased lung tissue. These results suggest the clinical utility of CAR in the targeted delivery of therapeutic compounds and imaging probes to PAH lungs.
authors.affiliation: Sanford-Burnham Medical Research Institute (formerly the Burnham Institute for Medical Research) at Lake Nona, Orlando, Florida, USA.
authors.forename: Takeo
authors.initials: T
authors.lastname: Urakami
authors.forename: Tero A H
authors.initials: TA
authors.lastname: Järvinen
authors.forename: Michie
authors.initials: M
authors.lastname: Toba
authors.forename: Junko
authors.initials: J
authors.lastname: Sawada
authors.forename: Namasivayam
authors.initials: N
authors.lastname: Ambalavanan
authors.forename: David
authors.initials: D
authors.lastname: Mann
authors.forename: Ivan
authors.initials: I
authors.lastname: McMurtry
authors.forename: Masahiko
authors.initials: M
authors.lastname: Oka
authors.forename: Erkki
authors.initials: E
authors.lastname: Ruoslahti
authors.forename: Masanobu
authors.initials: M
authors.lastname: Komatsu
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D016503:Drug Delivery Systems; D006801:Humans; D006976:Hypertension, Pulmonary / Q000150:complications / Q000473:pathology*; D000860:Hypoxia / Q000150:complications; D007211:Indoles / Q000494:pharmacology; D008168:Lung / Q000098:blood supply / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D008969:Molecular Sequence Data; D016686:Monocrotaline; D010455:Peptides / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D011651:Pulmonary Artery / Q000187:drug effects / Q000473:pathology*; D011758:Pyrroles / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors / Q000378:metabolism; D013997:Time Factors
chemical_list: D007211:Indoles; D010455:Peptides; D011758:Pyrroles; C116890:Semaxinib; D016686:Monocrotaline; D040262:Receptors, Vascular Endothelial Growth Factor