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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：
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
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/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

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.

摘要