Prodrugs targeting norepinephrine transporter for dual-selective therapy of refractory neuroblastoma

靶向去甲肾上腺素转运蛋白的前药用于难治性神经母细胞瘤的双重选择性治疗

• 批准号: 10189538
• 负责人: GARRETT M BRODEUR
• 金额: $ 62.3万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10189538
• 关键词: Acute; Address; Adverse effects; Affinity; Antineoplastic Agents; Automobile Driving; Biodistribution; Catecholamines; Cell Cycle; Cell Line; Cells; Chemistry; Chemoresistance; Chemosensitization; Child; Childhood Extracranial Solid Tumor; Clinical; Development; Disease; Disease model; Dose; Drug Delivery Systems; Drug usage; Evaluation; Exhibits; Exposure to; Genetically Engineered Mouse; Goals; Growth; Histone Deacetylase Inhibitor; Lead; Life; Ligands; Link; MYCN gene; Maximum Tolerated Dose; Mediating; Metastatic Pheochromocytoma; Modeling; Molecular; Molecular Target; Multi-Drug Resistance; Neoplasm Metastasis; Neoplasms; Neural Crest; Neuroblastoma; Neuroendocrine Cell; Neuroendocrine Tumors; Norepinephrine; Normal tissue morphology; Organ; Outcome; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Phenotype; Polymers; Primary Neoplasm; Process; Prodrugs; Radiation therapy; Radio; Radioactive; Radiopharmaceuticals; Refractory; Refractory Disease; Relapse; Research; Retinoids; Role; SN-38; Safety; Second Primary Cancers; Secondary to; Series; Solid Neoplasm; Structure; Structure-Activity Relationship; System; Targeted Radiotherapy; Testing; Therapeutic; Time; Tissues; Topoisomerase-I Inhibitor; Toxic effect; Translating; Translations; Treatment outcome; Tumor Tissue; Tumor-Derived; Type I DNA Topoisomerases; Validation; Water; Xenograft Model; Xenograft procedure; analog; antitumor effect; base; cancer cell; cancer therapy; cell injury; cell killing; clinical implementation; clinical translation; clinically relevant; combat; comparative; deiodination; design; disorder risk; drug action; effective therapy; effectiveness evaluation; experimental study; high risk; improved; irinotecan; metaiodobenzylguanidine; mimetics; neoplastic cell; neuroblastoma cell; neuroendocrine cancer; noradrenaline transporter; novel; novel strategies; pediatric patients; precursor cell; programs; refractory cancer; response; reuptake; small molecule; targeted delivery; therapeutic effectiveness; tool; treatment strategy; tumor; uptake

Abstract This project focuses on the design and evaluation of prodrugs with dual pharmacological selectivity, combining molecularly targeted mode of action with a tissue-specific, active uptake process (uptake-1) to enhance drug delivery to aggressive neuroendrocrine neoplasms, including high-risk neuroblastoma (NB) – the deadliest extracranial pediatric solid tumor currently lacking effective treatment options. Norepinephrine transporter (NET) driving accumulation of norepinephrine and its functional analogs is expressed by most solid tumors developing from sympathoadrenal precursor cells. However, tumor radiotherapy targeted to NET has shown limited efficiency, while causing serious adverse effects due to significant off-target distribution and extensive damage to healthy tissues. Centered on a dual-selective experimental drug delivery strategy integrating the uptake-1 process with a replication-dependent mode of drug action to confine the pharmacological effect to proliferative tumor cells expressing NET, this project aims to evaluate and optimize a pharmacotherapeutic approach designed to effectively combat refractory disease not responding to existing treatments, while minimizing toxicity to healthy organs and tissues. In our proof-of-concept experiments, a tripartite prodrug design integrating NET affinity with unique molecular targeting of a potent and selective topoisomerase I inhibitor was shown to be essential for achieving sustained intratumoral drug presence and markedly extended survival in clinically relevant models of aggressive neuroblastoma. Guided by these results, we hypothesize that dual-selective pharmacotherapy using NET-targeted prodrugs can provide a selective, safe and efficient way of treating different forms of high-risk disease. We also hypothesize that potency and selectivity of this approach will be enhanced by combining it with clinically proven small-molecule agents modulating tissue-specific expression of NET. These hypotheses will be tested by pursuing the following specific aims: Aim 1 studies will focus on comparative evaluation of polymeric carrier-linked prodrug constructs with regard to their cell uptake and growth inhibitory effects on primary NB cells and cell lines with different phenotypes, as a function of their molecular design and the potentiating action of the NET expression enhancing agents; Aim 2 and Aim 3 studies will comparatively evaluate the biodistribution profiles and therapeutic effectiveness of a series of tripartite prodrugs, with the goal to identify and optimize key construction variables, to establish feasibility of pharmacologically modulating NET expression for improving drug delivery and treatment outcomes, and to examine the roles of tumor phenotype and disease status in clinically relevant models of aggressive NB. The proposed research focusing on NET-targeted prodrugs equipped with dual pharmacological selectivity is significant by informing the development of a new strategy for treating aggressive NB and other refractory cancers.

摘要 本项目的重点是设计和评价具有双重药理选择性的前药， 将分子靶向作用模式与组织特异性主动摄取过程（摄取-1）相结合 增强对侵袭性神经内分泌肿瘤（包括高危神经母细胞瘤）的药物递送 (NB)- 目前缺乏有效治疗选择的最致命的颅外小儿实体瘤。 去甲肾上腺素转运蛋白（NET）驱动去甲肾上腺素及其功能类似物的积累， 由大多数由交感肾上腺前体细胞发展而来的实体瘤表达。然而，肿瘤 针对NET的放射治疗显示出有限的效率，同时由于 显著的脱靶分布和对健康组织的广泛损伤。以双选择为中心 整合摄取-1过程与复制依赖模式的实验性药物递送策略 将药理作用限制在表达NET的增殖性肿瘤细胞， 该项目旨在评估和优化一种旨在有效对抗 对现有治疗无反应的难治性疾病，同时最大限度地减少对健康器官的毒性， 组织中在我们的概念验证实验中，将NET亲和性与 一种有效的和选择性的拓扑异构酶I抑制剂的独特分子靶向被证明是 对于实现持续的肿瘤内药物存在和显著延长的生存期至关重要。 侵袭性神经母细胞瘤的临床相关模型。根据这些结果，我们假设， 使用NET靶向前药的双重选择性药物治疗可以提供选择性、安全和 治疗不同形式的高风险疾病的有效方法。我们还假设， 通过将其与临床证实的小分子药物结合， 调节NET的组织特异性表达的试剂。这些假设将通过以下方式进行检验： 以下具体目标：目标1研究将侧重于聚合物载体连接的比较评价， 前药构建体关于它们对原代NB细胞的细胞摄取和生长抑制作用的作用， 具有不同表型的细胞系，作为其分子设计和增强作用的函数， NET表达增强剂;目标2和目标3研究将比较评估 生物分布概况和治疗效果的一系列三方前药，目标是 确定并优化关键施工变量，以确定施工调整的可行性 NET表达用于改善药物递送和治疗结果，并检查肿瘤 表型和疾病状态的临床相关模型的侵袭性NB。拟议研究 关注具有双重药理学选择性的NET靶向前药是重要的， 为治疗侵袭性NB和其他难治性癌症的新策略的开发提供了信息。