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：
10441279
负责人：
GARRETT M BRODEUR
金额：
$ 61.05万
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/10441279
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

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.

抽象的该项目着重于具有双重药理学选择性的前药的设计和评估，将分子靶向的作用模式与组织特异性的活跃摄取过程（摄取1）相结合为了增强药物递送到侵略性神经内分泌肿瘤中，包括高危神经细胞瘤（NB） - 目前缺乏有效治疗方案的日期颅外小儿实体瘤。去甲肾上腺素转运蛋白（NET）驱动物的去甲肾上腺素的积累和功能类似物是IS IST 然而，大多数由交感神经前体细胞发展出来的实体瘤针对净的放射疗法显示出有限的功效，同时造成严重的不利影响对健康组织的明显脱靶分布和广泛的损害。实验性药物输送策略将摄取过程与复制依赖模式相结合药物作用以将药理学作用局限于表达网络的增生性肿瘤细胞，这项目旨在评估和优化旨在有效战斗的药物治疗方法难治性疾病不对现有治疗的反应，同时最大程度地减少对健康器官的毒性和在我们的概念证明实验中有效和选择性拓扑异构体II抑制剂的独特分子靶向是对于实现持续的肿瘤内药物的存在至关重要临床上相关的侵略性神经细胞瘤模型。使用净靶向前药的双重选择药物疗法可以提供选择器，安全且安全有效治疗不同形式的高风险疾病的方式。通过临床证明的小分子，将增强这种方法的选择性通过追求您的净的组织特异性表达的药物。以下具体目的：目标1研究将重点放在聚合物载体链接的比较评估上前药构建有关其细胞摄取的摄取和对原代NB细胞和生长的影响具有不同表型的细胞系，是其摩尔分子设计的函数以及净表达增强剂； AIM 2和AIM 3研究将评估您一系列三方前药的生物疗法概况和治疗有效性，其目标是识别并优化关键限制变异性，以确定药理学调节的可行性改善药物输送和信任结果的净表达，并检查肿瘤的作用积极的NB临床相关模型中的表型和疾病状态专注于装备有双重药理选择性的净靶向前药是重要的告知制定一种新的策略，以治疗积极的NB和其他难治性癌症。