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.

Target-seeking antifibrotic compound enhances wound healing and suppresses scar formation in mice

“…The CAR peptide also targets inflammation in the lungs (53). These findings suggest that CAR-targeted decorin could also have applications in the treatment of cancer and inflammatory conditions that involve TGF-β activity.…”

Liposomal Aerosols of Nitric Oxide (NO) Donor as a Long-Acting Substitute for the Ultra-Short-Acting Inhaled NO in the Treatment of PAH

“…Based on the success of liposomes as drug carriers and to address the unmet need for a long-acting NO formulation, we hypothesize that encapsulation of DN in liposomes modified with a homing peptide improves stability, and direct DN to concentrate and release NO in PAH lesions of the pulmonary vasculature. To test this hypothesis, we loaded the drug in pegylated liposomes modified with a cyclic homing peptide (CAR) containing 9 amino acids (CARSKNKDC), which has a half-life of 27 h and binds with the heparan sulfate–a glucosamino glycan, an endogenous substance involved in inflammatory process (29); this peptide also preferentially accumulates on PAH lungs (30). We evaluated DN entrapped CAR conjugated liposomes for physical properties, stability, release profiles, cellular uptake, lung accumulation, safety and pharmacological efficacy in cellular, ex-vivo and in vivo models.…”

Antenatal Hypoxia and Pulmonary Vascular Function and Remodeling

“…Designer peptides using targeting residues to focus drugs with widespread systemic effects, such as Rho-kinase inhibitors, to select cells is extremely promising. Recently, researchers designed a cyclic peptide, CARSKNKDC that selectively targeted active vascular remodeling in rat lungs due to monocrotaline or the combination of SU5416 and hypoxia [278]. Such selective drug targeting and delivery is ideal, since it combines therapeutic remodeling prevention with preservation of normal lung development.…”