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

• 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
• 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

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）：在此I阶段SBIR项目中，Parabon Nanolabs，Inc。（PNL）将生产出一种新颖的纳米药物化合物，优先选择和摧毁脑瘤干细胞（BTSC），以帮助胶质母细胞瘤多形式（GBM）治疗最大的脑瘤的治疗。 GBM中的BTSC已被确定为高度肿瘤细胞亚群，可促进肿瘤血管生成和治疗性抗性。例如，只有100个BTSC可以在小鼠模型中启动肿瘤生长，而来自同一肿瘤的100万个非茎细胞不能。无法消除具有当前护理标准的足够的BTSC，这可能是GBM复发率> 90％及其预后不良的率。使用Parabon的Essemblix“药物开发平台，将在专有的“分子面包板”（称为PNL24）上开发铅化合物及其实验变体，可以通过不同的靶向配体和细胞毒性有效载荷功能来实现“插件”的方式。单配体的替代方案。星形胶质细胞。 白喉毒素衍生物和结果通过标准的细胞毒性测定法测试了针对BTSC的功效和针对三种正常细胞系的安全性。最后，该化合物的抗BTSC疗效将通过对流增强输送（CED）在HBTSC内部异种移植小鼠模型中进行测试。如果发现既安全有效又有效，则该化合物将是随后的II期项目中未来研究的铅化合物，该项目研究了系统的毒性，PK和生物分布，以准备最终的IND应用。 公共卫生相关性：此I期SBIR项目将产生一种新型的纳米药物化合物，该化合物从胶质母细胞瘤多形（GBM）积极靶向和破坏脑瘤干细胞（BTSC），这是最致命的脑癌形式之一。 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.