Pulmonary arterial hypertension (PAH) is a debilitating and deadly disease of the pulmonary circulation; although relatively rare, PAH affects persons of every ethnic group, race, gender, and age, including newborns. Current anti-PAH medications (prostacyclin analogs, endothelin receptor antagonists, and phosphodiesterase-5 inhibitors) require cumbersome intravenous and subcutaneous injections, lack pulmonary selectivity, suffer from instability, produce systemic side effects, and fail to cur the underlying cause of the disease. Because PAH pathophysiology is entwined with multiple cellular and molecular pathways, single-drug therapy only modestly improves pulmonary hemodynamics and fails to restrain disease progression. Various combinations of anti-PAH drugs have recently been studied, but patient outcomes remain disappointing. Being predominantly vasodilators, the currently approved drugs do not reverse pulmonary vascular remodeling and abate right heart dysfunction, a major cause of deaths in PAH. We propose to circumvent indwelling catheter- and needle-based administration of drugs, intensify pulmonary selectivity, and reverse the pathogenesis of the disease to improve patient outcomes by formulating a combination of two drugs in nanocarriers equipped with a pulmonary homing device. We hypothesize that inhalable and targetable nanoparticles containing a vasodilator and an antioxidant will ameliorate pulmonary vasoconstriction, reverse pulmonary arterial remodeling, and abate right heart enlargement and failure in PAH. We will test this hypothesis by developing a targetable nanocarrier-based combination therapy that will simultaneously target two pathways of PAH pathogenesis: oxidative stress and Rho-kinase pathways. The system will consist of nanoparticles containing Cu/Zn superoxide dismutase, a superoxide scavenger, and fasudil, a Rho-kinase inhibitor and potent vasodilator. The outer surface of the particles will be coated with a cyclic peptide, CAR (CARSKNKDC), that accumulates preferentially in the hypertensive pulmonary arteries of PAH rats. We have generated compelling preliminary data in support of the central hypothesis of this project, and documented the feasibility of the delivery system in peer-reviewed publications. We will use various cellular, intact organ and rodent models of PAH to generate preclinical datastepping-stones for development of an efficacious drug therapyand address an unmet medical need. This work is highly innovative because ligand-equipped inhalable particles containing two drugs will relieve PAH symptoms, eliminate the need for needles and catheters, diminish systemic vasodilation, reverse vascular remodeling, attenuate right heart dysfunction, ease economic burdens, free patients from discomfort, and improve quality of life. The investigative team, comprising experts from pharmaceutical, biomedical, chemical, and clinical fields, is highly qualified to conduct the proposed studies. Our long-term goal is to translate this formulation from bench to bedside and develop an effective therapy, which would transform the current treatment modalities for PAH.

Public Health Relevance

Pulmonary arterial hypertension (PAH) is a rare, currently incurable disease. PAH is caused by constriction of the inner diameter of pulmonary arteries and arterioles, leading to restricted blood flow in the arteries of the lungs. In turn, the heart mst work harder to push blood through the narrowed pulmonary arteries. As a result, the heart becomes dangerously enlarged, and patients die of heart failure. Current anti-PAH drugs are not very effective, require intravenous and subcutaneous injections, multiple inhalations or oral administrations a day, expose the whole body to the drug, reduce systemic blood pressure, and precipitate cardiac arrest. We propose to develop a highly innovative system for combination therapy for PAH; this system will deliver two drugs directly to the pulmonary arteries, reduce systemic exposure of drugs, reverse heart dysfunction, eliminate the need for catheters and needles, enhance patient compliance, ease economic burdens, free patients from discomfort, and cure the underlying causes of this deadly disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL114677-04
Application #
9453024
Study Section
Respiratory Integrative Biology and Translational Research Study Section (RIBT)
Program Officer
Xiao, Lei
Project Start
2015-04-01
Project End
2019-03-31
Budget Start
2018-04-01
Budget End
2019-03-31
Support Year
4
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Texas Tech University
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
City
Lubbock
State
TX
Country
United States
Zip Code
79430
Rashid, Jahidur; Patel, Brijeshkumar; Nozik-Grayck, Eva et al. (2017) Inhaled sildenafil as an alternative to oral sildenafil in the treatment of pulmonary arterial hypertension (PAH). J Control Release 250:96-106
Nahar, Kamrun; Rashid, Jahidur; Absar, Shahriar et al. (2016) Liposomal Aerosols of Nitric Oxide (NO) Donor as a Long-Acting Substitute for the Ultra-Short-Acting Inhaled NO in the Treatment of PAH. Pharm Res 33:1696-710
Gupta, Nilesh; Patel, Brijeshkumar; Ahsan, Fakhrul (2014) Nano-engineered erythrocyte ghosts as inhalational carriers for delivery of fasudil: preparation and characterization. Pharm Res 31:1553-65