The goal of this project is to identify homing peptides that will deliver pharmacologic agents selectively to hypertensive pulmonary arteries and/or to specific sites (lesions) within the hypertensive pulmonary arterial bed. These or similar peptides can then hopefully be used to selectively treat the hypertensive pulmonary arteries of pulmonary arterial hypertension (PAH) patients to markedly improve their survival and quality of life. Despite recent advances in treatment, PAH is still debilitative and fatal. Thus, more effective therapeutic strategies are urgently needed. A major limitation in the systemic treatment of PAH patients with pharmacological agents is the lack of pulmonary vascular selectivity. For example, systemic hypotension is a serious limitation in the treatment of PAH patients with potent vasodilators. Thus, pulmonary arterial cell selective delivery would be an ideal route of administration for any PAH drug to reduce a drug's systemic adverse effects as well as to enhance its pulmonary vascular efficacy. It has been shown that there are distinctive cell surface markers in damaged/regenerated blood vessels, such as those in atherosclerotic lesions and tumors. These markers are recognized by specific homing peptides. Two specific homing peptides, CARSKNKDC (CAR) and CRKDKC (CRK), have been identified in wound microvasculature. Accumulating evidence suggests sustained Rho kinase-mediated pulmonary vasoconstriction is an important component of increased pulmonary vascular resistance in various animal models, as well as in human forms of PAH. The Rho kinase inhibitor, fasudil, more effectively reduces high pulmonary arterial pressure/resistance in rat models of PAH than do conventional vasodilators. However, fasudil does not have pulmonary vascular selectivity. Our encouraging preliminary results indicate that CAR also specifically homes to hypertensive pulmonary arteries in the hypertensive pulmonary arteries in the vascular endothelial growth factor receptor inhibitor (SU 5416)/hypoxia/normoxia-exposed rat model of severe PAH rats. Moreover, co-administration of CAR and the Rho kinase inhibitor fasudil markedly enhances the potency and pulmonary vasodilator selectivity of the fasudil. Given this background, we propose an integrated experimental approach to establish an effective hypertensive pulmonary arterial cell/tissue specific drug delivery system using homing peptides that specifically target these cells. This proposal focuses on the specific peptide, CAR, which our preliminary results suggest specifically recognizes hypertensive pulmonary arteries. We will use the recently developed SU5416/hypoxia/normoxia-exposed rat model of PAH, which closely resembles human PAH hemodynamically and histologically, to (1) determine whether CAR selectively binds to hypertensive pulmonary artery endothelial cells and/or to specific arterial lesions and (2) determine whether the intravenous co-administration of CAR and fasudil, and other vasodilators, causes selective pulmonary vasodilation, and determine the optimal dosing and timing of CAR and fasudil administrations in intact PAH rats.
A major limitation in the systemic treatment of pulmonary arterial hypertension with pharmacological agents is the lack of pulmonary vascular selectivity. This project aims at establishing an effective hypertensive pulmonary arterial cell/tissue specific drug delivery system using homing peptides that specifically target these cells/tissue to provide better clinical management of this disorder. This drug delivery system will enable the clinical use of potentially more effective treatments, such as the unconventional but potent vasodilator fasudil (a Rho kinase inhibitor), which have been avoided because of systemic adverse side effects.
|Toba, Michie; Alzoubi, Abdallah; O'Neill, Kealan D et al. (2014) Temporal hemodynamic and histological progression in Sugen5416/hypoxia/normoxia-exposed pulmonary arterial hypertensive rats. Am J Physiol Heart Circ Physiol 306:H243-50|
|Toba, Michie; Alzoubi, Abdallah; O'Neill, Kealan et al. (2014) A novel vascular homing peptide strategy to selectively enhance pulmonary drug efficacy in pulmonary arterial hypertension. Am J Pathol 184:369-75|
|Alzoubi, Abdallah; Almalouf, Philip; Toba, Michie et al. (2013) TRPC4 inactivation confers a survival benefit in severe pulmonary arterial hypertension. Am J Pathol 183:1779-1788|