Multimeric prodrugs for pulmonary hypertension therapy

用于肺动脉高压治疗的多聚体前药

• 批准号: 10287001
• 负责人: Michael Chorny
• 金额: $ 22万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10287001
• 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; Failure; 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; Ventricular; 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; pressure; prevent; primary pulmonary hypertension; response; small molecule; systemic toxicity; targeted delivery; uptake; vascular injury

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.

摘要 内皮屏障破坏的血管损伤是血管损伤的不可避免的后果。 导致肺动脉高压（PH）发展的病理过程。 尽管早期诊断和最近的临床治疗有所改善， 最终仍然是致命的，治疗效果差，预后差。围绕 开发一种有效和安全的治疗儿童PH的方法，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，以增强摄取并提供持久的治疗效果， 肺血管系统上的药物负荷，同时最大限度地减少脱靶分布， 全身毒性将使用非前列腺素类前列环素对该给药策略进行评价 作为小分子药物，它们已经显示出对PH的多效性作用。 然而，它们的临床实用性受到快速清除和显著性的限制。 全身不良反应。在我们先前关于靶向药物前药设计的工作的指导下， 具体交付和我们对该项目的原理验证研究结果，我们 假设设计为可逆组装、共价[聚合物- 药物]复合物将实现前列环素类似物的持续存在， 在肺组织中有足够的水平，导致PH的强烈和持久的抑制 在临床相关模型中的发展概括了疾病的关键特征。这 假设将得到检验，本项目的总体目标将通过以下方式实现： 以下具体目标：目标1研究将侧重于前药的体外评价， 比较确定它们对cAMP积累、血小板活化和生长的影响 增殖平滑肌细胞的动力学;目的2研究将比较检查 模型大分子构建体（Subaim 2a）的肺摄取和生物分布，和 在临床前模型中评价多聚体前药的治疗功效和毒性， PH（Subaim 2b）。这些研究预计将对该领域产生持久的影响， 证明了使用具有可裂解化学设计的多聚体前药 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 由于载体的积累的影响，并通过实施基于前药的递送， 增强选择性并延长合成的非- 前列腺素类前列环素模拟物作为一种实验性的新的治疗小儿肺 高血压-一种严重的、最终致命的疾病，缺乏治愈性治疗选择。