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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.

抽象的血管损伤伴内皮屏障破坏是血管损伤的不可避免的结果。导致肺动脉高压（PH）发展的病理过程。尽管诊断较早且临床管理近期有所改善，儿科 PH 最终仍然是致命的，治疗效果不佳，预后不佳。以为儿童 PH 开发一种有效且安全的疗法，这些研究将评估利用血管通透性增加的可裂解多聚体前药与这种病理学相关，以增强吸收并提供持久的治疗效果肺血管系统上的药物负载，同时最大限度地减少脱靶分布和全身毒性。该递送策略将用非前列腺素类前列环素进行评估对 PH 表现出多效性的模拟物。作为小分子药物，它们显示出在临床试验中有希望，但其临床效用受到快速清除和显着影响的限制全身性不良反应。以我们之前针对目标的前药设计工作为指导- 具体交付和我们对该项目的原理验证研究的结果，我们假设多聚体前药设计为可逆组装、共价[聚合物- [药物]复合物将在治疗上实现前列环素类似物的持续存在肺组织中的浓度足够，从而对 PH 产生强烈而持久的抑制开发概括该疾病主要特征的临床相关模型。这假设将得到检验，并且该项目的总体目标将通过追求来实现具体目标如下：目标 1 研究将重点关注前药的体外评价比较确定它们对 cAMP 积累、血小板活化和生长的影响平滑肌细胞增殖动力学；目标 2 研究将比较检验模型大分子结构（Subaim 2a）的肺部摄取和生物分布，以及在临床前模型中评估多聚体前药的治疗功效和毒性 PH（苏拜姆 2b）。这些研究预计将对该领域产生持久影响证明使用具有可裂解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，同时降低延迟不良反应的风险由于载体的积累而产生的影响，以及通过实施基于前药的递送增强选择性并延长合成非药物的药理活性持续时间前列腺素类前列环素模拟物作为小儿肺病的实验性新疗法高血压 - 一种严重的、最终致命的疾病，缺乏治疗选择。