Targetable and Inhalable Nanoparticle Based Combination Therapy for PAH

基于靶向和可吸入纳米颗粒的 PAH 联合疗法

• 批准号: 9040247
• 负责人: Fakhrul Ahsan
• 金额: $ 38.03万
• 依托单位: TEXAS TECH UNIVERSITY HEALTH SCIS CENTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9040247
• 关键词: Abate; Address; Adverse effects; Affect; Age; Antioxidants; Area; Arteries; Attenuated; Blood; Blood Circulation; Blood Vessels; Blood flow; Breathing; Caliber; Cardiac; Cardiomegaly; Cardiovascular system; Catheters; Cause of Death; Cell model; Chemicals; Clinical; Combined Modality Therapy; Cuprozinc Superoxide Dismutase; Cyclic Peptides; Data; Development; Devices; Disease; Disease Progression; Drug Delivery Systems; Drug Exposure; Drug Kinetics; Economic Burden; Edema; Encapsulated; Endothelin Receptor Antagonist; Ethnic group; Formulation; Frequencies; Functional disorder; Gender; Goals; Half-Life; Health; Heart; Heart Arrest; Heart failure; Homing; Hypoxia; Individual; Indwelling Catheter; Infusion procedures; Ingestion; Injection of therapeutic agent; Interruption; Intravenous; Laboratories; Lesion; Life; Ligands; Liposomes; Lung; Medical; Modality; Molecular; Monocrotaline; Morbidity - disease rate; Myocardial dysfunction; Needles; Newborn Infant; Oral; Oral Administration; Organ Model; Oxidative Stress; Pathogenesis; Pathway interactions; Patient-Focused Outcomes; Patients; Peer Review; Peptides; Peripheral; Persons; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacotherapy; Prostaglandins I; Publications; Pulmonary Circulation; Pulmonary Heart Disease; Pulmonary artery structure; Qualifying; Quality of life; Race; Rattus; Records; Rho-associated kinase; Rodent Model; Route; SOD2 gene; SU 5416; Safety; Scientist; Subcutaneous Injections; Superoxide Dismutase; Superoxides; Surface; Symptoms; System; Systemic blood pressure; Testing; Therapeutic Effect; Translating; Vascular remodeling; Vasodilation; Vasodilator Agents; Violence; Work; analog; arm; arterial remodeling; arteriole; base; bench to bedside; compliance behavior; constriction; effective therapy; efficacy testing; fasudil; hemodynamics; improved; inhibitor/antagonist; innovation; intravenous administration; intravenous injection; kinase inhibitor; liver injury; mimetics; mortality; nanocarrier; nanoparticle; nanoparticulate; particle; phosphodiesterase V; pre-clinical; pressure; prevent; pulmonary arterial hypertension; subcutaneous; uptake; vasoconstriction

 DESCRIPTION (provided by applicant): 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 data¿stepping-stones for development of an efficacious drug therapy¿and 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.

 描述（由申请人提供）：肺动脉高压（PAH）是一种使人衰弱和致命的肺循环疾病;虽然相对罕见，但PAH影响每个种族、种族、性别和年龄的人，包括新生儿。目前的抗PAH药物（前列环素类似物、内皮素受体拮抗剂和磷酸二酯酶-5抑制剂）需要繁琐的静脉内和皮下注射，缺乏肺选择性，具有不稳定性，产生全身副作用，并且不能治愈疾病的根本原因。由于PAH的病理生理学是由多种细胞和分子途径所组成的，因此单药治疗只能适度改善肺血流动力学，无法抑制疾病进展。最近研究了各种抗PAH药物的组合，但患者结局仍然令人失望。目前批准的药物主要是血管扩张剂，不能逆转肺血管重塑和减轻右心功能障碍，这是PAH死亡的主要原因。我们建议规避留置导管和针为基础的药物管理，加强肺的选择性，并扭转疾病的发病机制，以改善患者的治疗效果，通过制定两种药物的组合在纳米载体配备了肺归巢装置。我们假设，含有血管扩张剂和抗氧化剂的可吸入和靶向纳米颗粒将改善肺血管收缩，逆转肺动脉重塑，减轻PAH患者的右心扩大和衰竭。我们将通过开发一种可靶向的基于纳米载体的联合疗法来测试这一假设，该疗法将同时靶向PAH发病机制的两种途径：氧化应激和Rho激酶途径。该系统将由含有Cu/Zn超氧化物歧化酶（一种超氧化物清除剂）和法舒地尔（一种Rho激酶抑制剂和强效血管扩张剂）的纳米颗粒组成。颗粒的外表面将包被有环肽CAR（CARSKNKDC），其优先在PAH大鼠的高血压肺动脉中积累。我们已经产生了令人信服的初步数据来支持该项目的中心假设，并在同行评审的出版物中记录了该输送系统的可行性。我们将使用各种蜂窝， PAH的完整器官和啮齿动物模型，以生成临床前数据，为开发有效的药物治疗奠定基础，并解决未满足的医疗需求。这项工作具有高度创新性，因为含有两种药物的配体可吸入颗粒将缓解PAH症状，消除对针头和导管的需要，减少全身血管舒张，逆转血管重塑，减轻右心功能障碍，减轻经济负担，使患者免于不适，并改善生活质量。调查小组由来自制药、生物医学、化学和临床领域的专家组成，具有开展拟议研究的高素质。我们的长期目标是将该制剂从实验室转化为床边，并开发一种有效的治疗方法，这将改变PAH的当前治疗方式。