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The article ““A Novel Vascular Homing Peptide Strategy to Selectively Enhance Pulmonary Drug Efficacy in Pulmonary Arterial Hypertension” in the upcoming issue of The American Journal of Pathology, Volume 184, Number 2, February 2014 by Michie Toba, Abdallah Alzoubi, Kealan O’Neill, Kohtaro Abe, Takeo Urakami, Masanobu Komatsu, Diego Alvarez, Tero A.H. Jarvinen, David Mann, Erkki Ruoslahti, Ivan F. McMurtry, and Masahiko Oka describes how co-administered CAR selectively enhanced the pulmonary vascular effects of i.v. vasodilators in a Sugen5416/hypoxia/normoxia model of pulmonary arterial hypertension (PAH) . A major limitation in the pharmacological treatment of PAH is the lack of pulmonary vascular selectivity. Previous 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.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. These 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.
The paper, “Peptide-Directed Highly Selective Targeting of Pulmonary Arterial Hypertension” in American Journal of Pathology 2011; 178(6): 2489-2495, by Takeo Urakami, Tero A.H. Järvinen, Michie Toba, Junko Sawada, Namasivayam Ambalavanan, David Mann, Ivan McMurtry, Masahiko Oka, Erkki Ruoslahti, and Masanobu Komatsu describes the first discovery of a highly selective PAH-targeting and tissue-penetrating cyclic peptide CARSKNKDC (CAR). Injection of CAR resulted in the accumulation of the peptide in induced hypertensive lungs but not healthy lungs or other organs of the PAH rats. CAR also accumulated in various regions of the pulmonary system that play a crucial role in the development and pathogenesis of PAH. These findings support the future utility of CAR in the targeted delivery of therapeutic compounds and imaging probes to PAH lungs.
The paper “Target seeking antifibrotic compund enhances wound healing and surpresses scar formation in mice” in the Proceedings of the National Academy of Sciences 2010: Vol. 107, No. 50, 21671-21676, by Tero A.H. Järvinen and Erkki Ruoslahti describes a systemically administered, target-seeking biotherapeutic for scar prevention. The biotherapeutic consists of a vascular targeting peptide that specifically recognizes angiogenic blood vessels and extravasates into sites of injury, fused with a therapeutic molecule, decorin to prevent tissue fibrosis and promote tissue regeneration to reduce scarring.
The paper, “Molecular Changes in the Vasculature of Injured Tissues” in The American Journal of Pathology 2007: Vol. 171, No. 2, 702-711, by Tero A.H. Järvinen and Erkki Ruoslahti describes the initial discovery of the CAR cell penetrating peptide, its wound homing properties and usefulness in delivering treatments into regenerating tissues.