Mixed-Ligand Targeting of a Nano-Pharmaceutical Against GBM Stem Cells

纳米药物的混合配体靶向 GBM 干细胞

基本信息

批准号：
8201250
负责人：
Steven L Armentrout
金额：
$ 17.48万
依托单位：
PARABON NANOLABS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-26 至 2013-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8201250
关键词：
Accounting Adverse effects Affinity Astrocytes Binding Biodistribution Biological Assay Brain Brain Neoplasms Cell Count Cell Line Cell Surface Receptors Cells Confocal Microscopy Convection DNA Diphtheria Toxin Dose Dyes EGFR Protein Overexpression Engineering Epidermal Growth Factor Receptor Evaluation Exhibits Fluorescent Dyes Future Glioblastoma Government Human Human Cell Line Image In Vitro Inhibitory Concentration 50 Label Lead Ligands Malignant neoplasm of brain Mean Survival Times Measures Methods Molecular Mus Nanostructures Neurons Normal Cell Peptides Persons Pharmaceutical Preparations Pharmacologic Substance Phase Play Plug-in Preparation Recurrence Resistance Safety Small Business Innovation Research Grant Specificity Stem cells Structure Suggestion Test Result Testing Therapeutic Toxic effect Tracer Tumor Angiogenesis Tumor Stem Cells Variant Xenograft procedure brain cell cytotoxic cytotoxicity design drug development efficacy testing fluoromethyl 2,2-difluoro-1-(trifluoromethyl)vinyl ether improved in vitro testing in vivo mouse model nano nanocarrier nanocompound neoplastic cell nerve stem cell novel outcome forecast overexpression peptide E (adrenal medulla)peptide P preference receptor receptor binding standard of care stem targeted delivery tumor tumor growth tumor specificity tumorigenic

项目摘要

DESCRIPTION (provided by applicant): In this Phase I SBIR project, Parabon NanoLabs, Inc. (PNL) will produce a novel, nano- pharmaceutical compound that preferentially selects and destroys brain tumor stem cells (BTSCs) to aid the treatment of glioblastoma multiforme (GBM), one of the most lethal brain cancers. BTSCs in GBM have been identified as a highly tumorigenic cell subpopulation that promotes tumor angiogenesis and therapeutic resistance. For example, as few as 100 BTSCs can initiate tumor growth in a mouse model, whereas 1 million non-stem cells from the same tumor cannot. The inability to eliminate sufficient BTSCs with the current standard of care may account for the >90% recurrence rate of GBM and its poor prognosis. Using Parabon's Essemblix" Drug Development Platform, the lead compound and its experimental variants will be developed upon a proprietary "molecular breadboard," called PNL24, that can be functionalized with different targeting ligands and cytotoxic payloads in "plug and play" fashion. These compounds will be used to test the hypothesis that mixed-ligand, low-affinity targeting can achieve superior BTSC targeting specificity versus single-ligand alternatives. To test BTSC specificity, three targeting compounds will be created by functionalizing PNL24 with one of two different targeting ligands and a combination of both. Dye-labeling of each compound will be used to test in vitro targeting specificity, measured via fluorescent confocal microscopy, against BTSC and normal human cell lines serving as controls, specifically, neural stem cells, neurons and astrocytes. The most selective of the three targeting structures (hypothetically the mix-ligand construct) wil be further functionalized with a diphtheria toxin derivative and the result tested for efficacy against BTSC and safety against three normal cell lines via standard cytotoxicity assay. Finally, the anti-BTSC efficacy of this compound will be tested in a hBTSC intracranial xenograft mouse model via convection-enhanced delivery (CED). If found to be both safe and effective, this compound will be the lead compound for future studies in a subsequent Phase II project that examines systematic toxicity, PK and biodistribution in preparation for an eventual IND application. PUBLIC HEALTH RELEVANCE: This Phase I SBIR project will produce a novel nano-pharmaceutical compound that actively targets and destroys brain tumor stem cells (BTSCs) from glioblastoma multiforme (GBM), one of the most lethal forms of brain cancer. Built using the Essemblix" Drug Development Platform, which enables first-of-its-kind "plug and play" molecular engineering, an actively targeted nano-compound and experimental variants with different targeting components, will be produced. The compounds will be tested against representative cell lines and a mouse model to demonstrate selective targeting and destruction of BTSCs, and negligible toxicity to normal brain cells.

描述（由申请人提供）：在该 I 期 SBIR 项目中，Parabon NanoLabs, Inc. (PNL) 将生产一种新型纳米药物化合物，该化合物优先选择并破坏脑肿瘤干细胞 (BTSC)，以帮助治疗多形性胶质母细胞瘤（GBM），最致命的脑癌之一。 GBM 中的 BTSC 已被确定为高度致瘤细胞亚群，可促进肿瘤血管生成和治疗耐药性。例如，在小鼠模型中，只需 100 个 BTSC 就可以启动肿瘤生长，而来自同一肿瘤的 100 万个非干细胞则不能。目前的护理标准无法消除足够的 BTSC，这可能是 GBM 复发率 >90% 及其不良预后的原因。使用 Parabon 的 Essemblix“药物开发平台，先导化合物及其实验变体将在称为 PNL24 的专有“分子面包板”上开发，该“分子面包板”可以以“即插即用”的方式与不同的靶向配体和细胞毒性有效负载一起功能化。这些化合物将用于测试混合配体、低亲和力靶向可以实现比单一配体替代方案更优异的 BTSC 靶向特异性的假设。为了测试 BTSC 特异性，将使用三种靶向化合物。通过用两种不同的靶向配体之一对 PNL24 进行功能化而创建，并且每种化合物的染料标记将用于测试体外靶向特异性，通过荧光共聚焦显微镜测量，针对作为对照的 BTSC 和正常人类细胞系。具体来说，三种靶向结构中最具选择性的神经干细胞、神经元和星形胶质细胞将被进一步功能化。白喉毒素衍生物，并通过标准细胞毒性测定测试了针对 BTSC 的功效和针对三种正常细胞系的安全性。最后，将通过对流增强递送 (CED) 在 hBTSC 颅内异种移植小鼠模型中测试该化合物的抗 BTSC 功效。如果发现该化合物既安全又有效，那么该化合物将成为后续 II 期项目未来研究的先导化合物，该项目检查系统毒性、PK 和生物分布，为最终的 IND 申请做准备。公共健康相关性：第一阶段 SBIR 项目将生产一种新型纳米药物化合物，该化合物可主动靶向并破坏来自多形性胶质母细胞瘤 (GBM) 的脑肿瘤干细胞 (BTSC)，多形性胶质母细胞瘤 (GBM) 是最致命的脑癌形式之一。使用 Essemblix“药物开发平台构建，该平台实现了首个“即插即用”分子工程，将生产一种主动靶向纳米化合物和具有不同靶向成分的实验变体。这些化合物将针对代表性细胞系和小鼠模型，证明 BTSC 的选择性靶向和破坏，以及对正常脑细胞的毒性可忽略不计。