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

描述（由申请人提供）：在这个一期SBIR项目中，Parabon NanoLabs, Inc. （PNL）将生产一种新型的纳米药物化合物，该化合物可以优先选择和破坏脑肿瘤干细胞（BTSCs），以帮助治疗多形性胶质母细胞瘤（GBM），这是最致命的脑癌之一。GBM中的BTSCs已被确定为一种高度致瘤性的细胞亚群，可促进肿瘤血管生成和治疗耐药性。例如，在小鼠模型中，只有100个BTSCs可以启动肿瘤生长，而来自同一肿瘤的100万个非干细胞却不能。目前的治疗标准无法清除足够的BTSCs，这可能是GBM复发率高达90%且预后不良的原因。利用Parabon的Essemblix“药物开发平台”，先导化合物及其实验变体将在一个名为PNL24的专有“分子面包板”上开发，该面包板可以通过“即插即用”的方式与不同的靶向配体和细胞毒性有效载荷进行功能化。这些化合物将用于验证混合配体，低亲和力靶向可以比单一配体替代品获得更好的BTSC靶向特异性的假设。为了测试BTSC的特异性，将用两种不同的靶向配体中的一种或两者的组合来功能化PNL24，从而产生三种靶向化合物。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BTSC和作为对照的正常人类细胞系，特别是神经干细胞，神经元和星形胶质细胞。三种靶向结构中最具选择性的（假设为混合配体结构）将被a进一步功能化

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.