Targeted Delivery of a Novel Synthetic Curcumin Analog, EF24 to Glioblastoma and

新型合成姜黄素类似物 EF24 靶向递送至胶质母细胞瘤和

• 批准号: 8112281
• 负责人: DANIEL J BRAT
• 金额: $ 16.86万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-01 至 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8112281
• 关键词: Address; Affinity; Apoptosis; Astrocytoma; Binding; Blood - brain barrier anatomy; Blood Vessels; Brain; Brain Neoplasms; Cell Cycle Arrest; Cell Surface Receptors; Cells; Crohn' s disease; Curcumin; Cytotoxic agent; Diabetic Retinopathy; Disease; Doctor of Medicine; Doctor of Philosophy; Drug usage; Endothelial Cells; Factor VIIa; Fluorescence; Genetic Transcription; Glioblastoma; Glioma; Growth; Histocytochemistry; Human; Hyperplasia; Hypoxia; In Vitro; Label; Lead; Length; Ligands; Link; M cell; MDM2 gene; Macular degeneration; Malignant - descriptor; Malignant Glioma; Malignant Neoplasms; Matrix Metalloproteinases; Modeling; Mus; Nature; Necrosis; Neoplastic Endothelial Cell; Nervous system structure; PTEN gene; Patients; Pharmaceutical Preparations; Primary Brain Neoplasms; Production; Psoriasis; Signal Pathway; Specificity; Specimen; Streptavidin; Therapeutic; Thromboplastin; Thrombosis; Time; Tissues; Tumor Angiogenesis; United States; Up-Regulation; Vascular Endothelial Cell; Vascular Endothelial Growth Factors; Vascular Endothelium; Xenograft Model; Xenograft procedure; analog; angiogenesis; caspase-3; caspase-8; cytotoxic; drug distribution; drug efficacy; endometriosis; in vivo; innovation; neoplastic cell; novel; novel strategies; novel therapeutic intervention; optical imaging; receptor mediated endocytosis; release factor; response; targeted delivery; tumor; tumor growth

DESCRIPTION (provided by applicant): Glioblastoma (GBM) is the most common primary brain tumor and the most malignant form of astrocytoma (WHO grade IV). We have demonstrated that both GBM tumor cells and its vascular endothelium express the cell surface receptor tissue factor (TF), a critical initiator of thrombosis, while the vasculature of the normal brain does not. Here we explore mechanisms related to the upregulation of TF in the vasculature of GBM and hypothesize that a cytotoxic agent conjugated to a carrier directed at TF will specifically target blood vessels of GBM, but not non-neoplastic brain. Thus, the objective of this proposal is to develop a novel therapeutic approach for GBM, in which the TF-expressing vasculature is specifically targeted. The cytotoxic agent we have developed is EF24, a synthetic curcumin analog, which will be linked to enzymatically inactive coagulation factor VIIa (fVIIa), the high affinity ligand for TF that has exquisite specificity. We hypothesize that this drug conjugate (EF24-FFRck-fVIIa) will bind to TF on vascular endothelial cells (VECs) within the GBM, enter target cells by ligand-receptor mediated endocytosis, and elicit a cytotoxic response. The disruption of the blood brain barrier (BBB) due to targeting the VECs and to the tissue-destructive nature of GBM should also permit binding of the drug-conjugate directly to TF expressing neoplastic cells. Thus, this therapeutic approach has a high likelihood of having both an anti-angiogenic and direct anti-tumor effect. Specific Aim I will determine the mechanisms by which malignant gliomas induce the expression of TF by vascular endothelial cells. We will establish whether PTEN loss and hypoxia lead to release of factors by gliomas that induce endothelial TF expression in vitro and will determine if these mechanisms have correlates in human brain tumor specimens. Aim II will establish the distribution of the drug-conjugate and the drug in glioma xenografts, their associated vasculature and the adjacent normal brain. Near infrared optical imaging will be used to determine the distribution of the drug-conjugate in vitro and in vivo using Cy5.5-labeled EF24-FFRck- fVIIa. The distribution of the drug using biotinylated EF24 combined with streptavidin histochemistry will be used to more precisely localize the drug in glioma xenografts tissue sections. Aim III will determine the efficacy of the drug-conjugate against malignant gliomas in a mouse xenograft model. We will examine the effects of the EF24-FFRck-fVIIa on survival in this model and examine the biologic correlates of drug-conjugate treatment, including tumor growth, angiogenesis and disruption of the BBB. PUBLIC HEALTH RELEVANCE: Glioblastoma (GBM) is the most common primary brain tumor, with 8700 new cases per year in the United States. These tumors are universally fatal and the average length of patient survival is only 60 weeks with current therapies. This proposal uses a highly innovative approach to specifically target the abnormal blood vessels of GBM in order to slow their growth. Although this proposal specifically addresses the abnormal vessels in GBM, the approach may find application in other diseases with abnormal blood vessel growth, such as diabetic retinopathy, macular degeneration, endometriosis, Crohn's disease, psoriasis, and other cancers.

描述（由申请人提供）：胶质母细胞瘤（GBM）是最常见的原发性脑肿瘤，也是星形细胞瘤中最恶性的一种（WHO IV级）。我们已经证明，GBM肿瘤细胞及其血管内皮细胞表达细胞表面受体组织因子（TF），血栓形成的关键启动子，而正常大脑的血管系统不。在这里，我们探讨了与TF在GBM的血管系统中上调相关的机制，并假设与针对TF的载体缀合的细胞毒性剂将特异性靶向GBM的血管，但不靶向非肿瘤性脑。因此，本提案的目的是开发一种新的GBM治疗方法，其中特异性靶向表达TF的脉管系统。我们已经开发的细胞毒性剂是EF 24，一种合成的姜黄素类似物，它将与无酶活性的凝血因子VIIa（fVIIa）连接，该凝血因子VIIa是TF的高亲和力配体，具有精致的特异性。我们假设这种药物偶联物（EF 24-FFRck-fVIIa）将结合GBM内血管内皮细胞（VEC）上的TF，通过配体-受体介导的内吞作用进入靶细胞，并引发细胞毒性应答。由于靶向VEC和GBM的组织破坏性而对血脑屏障（BBB）造成的破坏也应该允许药物缀合物直接与表达TF的肿瘤细胞结合。因此，这种治疗方法具有抗血管生成和直接抗肿瘤作用的高可能性。具体目的我将确定恶性胶质瘤诱导血管内皮细胞表达TF的机制。我们将确定是否PTEN的损失和缺氧导致释放的因素，诱导内皮TF表达的胶质瘤在体外，并将确定这些机制是否有相关的人脑肿瘤标本。目的II将建立药物偶联物和药物在胶质瘤异种移植物、其相关血管和邻近正常脑中的分布。近红外光学成像将用于使用Cy5.5标记的EF 24-FFRck- fVIIa在体外和体内确定药物缀合物的分布。使用生物素化EF 24结合链霉亲和素组织化学的药物分布将用于更精确地定位神经胶质瘤异种移植组织切片中的药物。目的III将在小鼠异种移植模型中确定药物缀合物针对恶性神经胶质瘤的功效。我们将检查EF 24-FFRck-fVIIa对该模型中存活率的影响，并检查药物缀合物治疗的生物学相关性，包括肿瘤生长、血管生成和BBB破坏。 胶质母细胞瘤（GBM）是最常见的原发性脑肿瘤，在美国每年有8700例新发病例。这些肿瘤普遍是致命的，患者的平均生存期只有60周。该提案使用了一种高度创新的方法，专门针对GBM的异常血管，以减缓其生长。尽管该提议具体针对GBM中的异常血管，但该方法可以应用于具有异常血管生长的其他疾病，例如糖尿病视网膜病变、黄斑变性、子宫内膜异位症、克罗恩病、牛皮癣和其他癌症。