Multimeric prodrugs for pulmonary hypertension therapy

摘要 血管损伤伴随内皮细胞屏障的破坏是一种不可避免的后果 导致肺动脉高压(PH)的病理过程。 尽管早期诊断和最近的临床处理有所改善，但儿童PH 最终仍然是致命的，治疗结果很差，预后很差。以…为中心 开发一种有效且安全的儿童肺高压治疗方法，这些研究将评估 利用血管通透性增加的可切割多聚体前药 以增强摄取并提供持久的治疗效果 将药物在肺血管系统上的载药量降至最低，同时将靶外分布降至最低 全身毒性。这种给药策略将用非前列腺素前列环素进行评估 对PH表现出多效性的模拟物。作为小分子药物，他们已经证明 在临床试验中很有希望，然而它们的临床应用受到快速清除和显著 系统性不良影响。根据我们之前在靶向前药设计方面的工作- 具体交付和我们对该项目的原则证明研究的结果，我们 假设多聚体前体药物设计为可逆组装的共价[聚合物- 药物]复合体将在治疗上实现前列环素类似物的持续存在 肺组织中的适当水平，导致对PH的强烈和持久的抑制 临床相关模型的发展，概括了该病的主要特征。这 将检验假设，并通过追求实现本项目的总体目标 具体目标如下：目标1研究将重点放在通过以下方式对前药进行体外评价 比较测定它们对cAMP积聚、血小板活化和生长的影响 增殖的平滑肌细胞的动力学；Aim 2研究将比较检查 模型大分子结构(Subaim 2a)的肺摄取和生物分布，以及 在临床前模型中评价多聚体前体药物的治疗效果和毒性 PH(Subaim 2b)。这些研究预计将在#年对实地产生持久影响。 论证使用具有可切割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，同时降低迟发性不良反应的风险 由于载体的积累而产生的影响，以及通过实施基于前药物的给药来 提高非合成化合物的选择性并延长其药理活性持续时间 前列腺素类前列环素类似物治疗儿童肺部疾病的实验研究 高血压-一种严重的、最终致命的疾病，缺乏根本性的治疗选择。

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.