Multimeric prodrugs for pulmonary hypertension therapy

用于肺动脉高压治疗的多聚体前药

基本信息

批准号：
10475200
负责人：
Michael Chorny
金额：
$ 26.4万
依托单位：
CHILDREN'S HOSP OF PHILADELPHIA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-01 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10475200
关键词：
Address Adverse effects Adverse event Affect Animal Model Arterial Disorder Biocompatible Materials Biodistribution Biology Blood Vessels Cardiopulmonary Characteristics Chemicals Child Childhood Clinical Clinical Management Clinical Trials Complex Cyclic AMP Development Disease Disease Progression Doctor of Philosophy Dose Drug Delivery Systems Drug Targeting Early Diagnosis Effectiveness Endothelium Epoprostenol Evaluation Exhibits Family Formulation Functional disorder Genetic Growth Histologic Hypoxia In Situ In Vitro Inflammatory Injury Kinetics Link Lung Lung diseases Modality Modeling Pathogenesis Pathologic Pathologic Processes Pathology Pathway interactions Patients Pediatric cardiology Permeability Pharmaceutical Preparations Pharmacology Pharmacotherapy Platelet Activation Polymers Pre-Clinical Model Prodrugs Prognosis Prostaglandins I Pulmonary Hypertension Risk Safety Signal Transduction Site Smooth Muscle Myocytes Specificity Structure of parenchyma of lung System Testing Therapeutic Therapeutic Agents Therapeutic Effect Tissues Toxic effect Translations Treatment Efficacy Treatment outcome Treatment-related toxicity Vascular Diseases Vascular Endothelial Growth Factors Vascular Permeabilities Work analog arm arterial remodeling base body system cell growth chemical synthesis clinical implementation clinically relevant comparative congenital heart disorder curative treatments design drug clearance ethylene glycol hemodynamics human disease improved in vivo meetings mimetics mouse model novel pleiotropism prevent primary pulmonary hypertension pulmonary arterial pressure pulmonary vascular disorder response right ventricular failure small molecule systemic toxicity targeted delivery uptake vascular injury

项目摘要

Abstract Vascular injury with disruption of the endothelial barrier is an inevitable consequence of the pathological processes contributing to the development of pulmonary hypertension (PH). Despite earlier diagnosis and recent improvements in its clinical management, pediatric PH remains ultimately fatal, with poor treatment outcomes and dismal prognosis. Centered on developing an effective and safe therapy for PH in children, these studies will evaluate cleavable multimeric prodrugs taking advantage of the increased vascular permeability associated with this pathology to enhance uptake and provide a lasting therapeutic effect of the drug cargo on the pulmonary vasculature, while minimizing off-target distribution and systemic toxicity. This delivery strategy will be evaluated with non-prostanoid prostacyclin mimetics exhibiting pleiotropic effects against PH. As small-molecule drugs, they have shown promise in clinical trials, however their clinical utility is limited by rapid clearance and significant systemic adverse effects. Guided by our prior work on the design of prodrugs for target- specific delivery and the results of our proof-of-principle studies toward this project, we hypothesize that multimeric prodrugs designed as reversibly assembled, covalent [polymer- drug] complexes will achieve sustained presence of the prostacyclin analogs at therapeutically adequate levels in the lung tissue, resulting in a strong and lasting suppression of the PH development in a clinically relevant model recapitulating key features of the disease. This hypothesis will be tested and the overall objective of this project will be attained by pursuing the following specific aims: Aim 1 studies will focus on in vitro evaluation of the prodrugs by comparatively determining their effects on cAMP accumulation, platelet activation, and growth kinetics of proliferative smooth muscle cells; Aim 2 studies will comparatively examine pulmonary uptake and biodistribution of a model macromolecular construct (Subaim 2a), and evaluate therapeutic efficacy and toxicity of the multimeric prodrugs in a preclinical model of PH (Subaim 2b). These studies are expected to have a lasting impact on the field by demonstrating feasibility of using multimeric prodrugs with a cleavable chemical design to improve safety and effectiveness of drug therapy while mitigating the risk for delayed adverse effects due to accumulation of the carrier, and by implementing prodrug-based delivery to enhance selectivity and extend the duration of the pharmacological activity of synthetic non- prostanoid prostacyclin mimetics as an experimental new treatment for pediatric pulmonary hypertension - a severe, ultimately fatal disease lacking curative treatment options.

抽象的内皮屏障的干扰是血管损伤是不可避免的结果有助于肺动脉高压发展的病理过程（pH）。尽管较早的诊断和临床管理的最新改善，但小儿pH值最终仍然致命，治疗结果和预后惨淡。以中心为中心为儿童开发有效且安全的疗法，这些研究将评估可裂解的多聚体前药利用了增加的血管渗透性与这种病理学相关，以增强摄取并提供持久的治疗作用肺脉管系统上的吸毒货物，同时最大程度地减少靶向分布和全身毒性。将使用非肉酱前列环素评估此交付策略模拟物具有对pH的多效作用。作为小分子药物，它们已经显示在临床试验中的承诺，但是它们的临床实用性受到快速清除和显着的限制系统性不良影响。在我们先前在设计目标设计方面的工作的指导下 - 具体的交付和我们对该项目的原理证明研究结果，我们假设将多聚体前药设计为可逆组装的共价[聚合物 - 药物]复合物将在治疗中实现前列环蛋白类似物的持续存在肺组织中足够的水平，导致pH值强烈持久在临床相关模型中的发展，概括了该疾病的关键特征。这假设将进行检验，该项目的总体目标将通过追求来实现以下具体目的：AIM 1研究将专注于对前药的体外评估比较确定其对cAMP积累，血小板激活和生长的影响增殖平滑肌细胞的动力学； AIM 2研究将相对检查模型大分子构建体的肺摄取和生物分布（Subaim 2a）和评估多聚体前药的治疗功效和毒性 pH（Subaim 2b）。预计这些研究将对该领域产生持久的影响证明使用具有可切合化学设计的多聚体前药的可行性提高药物治疗的安全性和有效性，同时减轻延迟不良风险由于载体的积累以及实施基于前药的交付而引起的影响提高选择性并延长合成非 - 药理活性的持续时间前列腺素的前列腺素模拟物作为小儿肺的实验新疗法高血压 - 一种严重的，最终缺乏治疗方法的致命疾病。