权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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：
10655349
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/10655349
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 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 Radioactive Radiopharmaceuticals Refractory Refractory Disease Relapse Research Retinoids Role SN-38 Safety Second Primary Cancers 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 Type I DNA Topoisomerases Validation Water Xenograft Model Xenograft procedure analog antitumor effect 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 pharmacologic 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.

摘要该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相结合(摄取-1) 加强对侵袭性神经内分泌肿瘤的药物输送，包括高危神经母细胞瘤 (NB)-目前缺乏有效治疗选择的最致命的儿童颅外实体肿瘤。去甲肾上腺素转运体(NET)驱动去甲肾上腺素及其功能类似物的蓄积大多数由交感神经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疗效，同时由于以下原因造成严重的不良反应严重偏离目标的分布和对健康组织的广泛损害。以双重选择为中心将摄取-1过程与复制依赖模式相结合的实验性给药策略药物作用仅限于表达Net的增殖性肿瘤细胞，这该项目旨在评估和优化一种旨在有效对抗顽固性疾病对现有治疗无效，同时将对健康器官的毒性降至最低纸巾。在我们的概念验证实验中，将净亲和力和一种有效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是必不可少的侵袭性神经母细胞瘤的临床相关模型。在这些结果的指导下，我们假设使用网络靶向前体药物的双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危疾病的有效方法。我们还假设，效力和这种方法的选择性将通过将其与临床证明的小分子相结合来增强调节Net的组织特异性表达的试剂。这些假说将通过追求以下具体目标：目标1研究将侧重于聚合物载体连接的比较评价前药构造物对原代NB细胞的摄取和生长抑制作用不同表型的细胞系，作为其分子设计和增强作用的函数净表达增强剂；目标2和目标3研究将比较评估一系列三方前药的生物分布和治疗效果，目的是识别和优化关键结构变量，建立药物调控的可行性 NET表达改善药物传递和治疗结果，并检查肿瘤的作用侵袭性神经营养不良临床相关模型的表型和疾病状态。拟议的研究关注具有双重药理选择性的净靶向前药具有重要意义为开发治疗侵袭性NB和其他难治性癌症的新策略提供信息。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Structural Optimization and Enhanced Prodrug-Mediated Delivery Overcomes Camptothecin Resistance in High-Risk Solid Tumors.

DOI：
10.1158/0008-5472.can-20-1344
发表时间：
2020-10-01
期刊：
Cancer research
影响因子：
11.2
作者：
Nguyen F;Guan P;Guerrero DT;Kolla V;Naraparaju K;Perry LM;Soberman D;Pressly BB;Alferiev IS;Chorny M;Brodeur GM
通讯作者：
Brodeur GM

Nanocarrier-Based Delivery of SN22 as a Tocopheryl Oxamate Prodrug Achieves Rapid Tumor Regression and Extends Survival in High-Risk Neuroblastoma Models.

DOI：
10.3390/ijms23031752
发表时间：
2022-02-03
期刊：
International journal of molecular sciences
影响因子：
5.6
作者：
Alferiev IS;Guerrero DT;Soberman D;Guan P;Nguyen F;Kolla V;Fishbein I;Pressly BB;Brodeur GM;Chorny M
通讯作者：
Chorny M

Poloxamer-linked prodrug of a topoisomerase I inhibitor SN22 shows efficacy in models of high-risk neuroblastoma with primary and acquired chemoresistance.

DOI：
10.1096/fj.202101830rr
发表时间：
2022-03
期刊：
FASEB journal : official publication of the Federation of American Societies for Experimental Biology
影响因子：
0
作者：
Alferiev IS;Guerrero DT;Guan P;Nguyen F;Kolla V;Soberman D;Pressly BB;Fishbein I;Brodeur GM;Chorny M
通讯作者：
Chorny M

Robust Chemical Strategy for Stably Labeling Polyester-Based Nanoparticles with BODIPY Fluorophores.

可稳定的化学策略，可稳定地将基于聚酯的纳米颗粒标记为荧光团。