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

基本信息

批准号：
10033345
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
项目类别：
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/10033345
关键词：
Acute Address Adverse effects Affinity Antineoplastic Agents Automobile Driving Biodistribution Catecholamines Cell Cycle Cell Line Cells Chemistry 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 Malignant Neoplasms 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 response reuptake small molecule targeted delivery therapeutic effectiveness tool treatment strategy tumor uptake

项目摘要

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.

抽象的该项目重点关注具有双重药理选择性的前药的设计和评价，将分子靶向作用模式与组织特异性主动摄取过程相结合 (uptake-1) 增强对侵袭性神经内分泌肿瘤（包括高危神经母细胞瘤）的药物输送 (NB) – 最致命的颅外儿童实体瘤，目前缺乏有效的治疗方案。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大多数由交感肾上腺前体细胞发展而来的实体瘤表达。针对 NET 的放射治疗显示出有限的效率，同时由于以下原因造成严重的副作用以双重选择性为中心的显着脱靶分布和对健康组织的广泛损害。将摄取 1 过程与复制依赖模式相结合的实验药物递送策略药物作用限制药理学作用于表达 NET 的增殖性肿瘤细胞，这该项目旨在评估和优化旨在有效对抗对现有治疗没有反应的难治性疾病，同时最大限度地减少对健康器官的毒性和在我们的概念验证实验中，将 NET 亲和力与组织相结合的三方前药设计。有效且选择性的拓扑异构酶 I 抑制剂的独特分子靶向被证明对于实现持续的瘤内药物存在和显着延长生存期至关重要在这些结果的指导下，我们研究了侵袭性神经母细胞瘤的临床相关模型。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也与这种效力作斗争。通过与临床证明的小分子相结合，该方法的选择性将得到增强调节 NET 组织特异性表达的药物将通过追求以下结果进行检验。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估前药构建体对原代 NB 细胞的细胞摄取和生长抑制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；Aim 2和Aim 3研究将比较评估一系列三方前药的生物分布曲线和治疗效果，目的是确定并优化关键构建变量，以确定药理调节的可行性 NET 表达以改善药物输送和治疗结果，并检查肿瘤的作用侵袭性 NB 临床相关模型的表型和疾病状态。专注于具有双重药理选择性的 NET 靶向前药具有重要意义为治疗侵袭性 NB 和其他难治性癌症的新策略的开发提供信息。