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: 8223183
• 负责人: DANIEL J BRAT
• 金额: $ 20.23万
• 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 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8223183
• 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; public health relevance; 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和最恶性的星形胶质细胞瘤（WHO IV级）。我们已经证明，GBM肿瘤细胞及其血管内皮都表达了细胞表面受体组织因子（TF），这是血栓形成的关键引发剂，而正常脑的脉管系统却没有。在这里，我们探索了与GBM脉管系统中TF上调有关的机制，并假设与针对TF的载体结合的细胞毒性剂将特异性地靶向GBM的血管，而不是非塑性脑的血管。因此，该提案的目的是为GBM开发一种新型的治疗方法，在该方法中，表达TF的脉管系统是专门针对的。我们开发的细胞毒性剂是EF24，一种合成姜黄素类似物，它将与酶无活性凝血因子VIIA（FVIIA）相关，这是具有精致特异性的TF的高亲和力配体。我们假设该药物结合物（EF24-FFRCK-FVIIA）将与GBM内血管内皮细胞（VEC）上的TF结合，并通过配体受体介导的内吞作用进入靶细胞，并引起细胞毒性反应。由于靶向VEC和GBM的组织破坏性而导致的血脑屏障（BBB）的破坏还应允许直接与表达肿瘤细胞的TF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很高可能性。具体目的我将确定恶性神经胶质瘤通过血管内皮细胞诱导TF表达的机制。我们将确定PTEN丢失和缺氧是否导致因胶质瘤释放因素，从而在体外诱导内皮TF表达，并确定这些机制是否在人脑肿瘤标本中相关。 AIM II将在神经胶质瘤异种移植物，相关的脉管系统和邻近的正常脑中建立药物缀合物和药物的分布。近红外光学成像将使用CY5.5标记的EF24-FFRCK-FVIIA在体外和体内确定药物偶联物的分布。使用生物素化的EF24与链霉亲和素组织化学结合的药物分布将更精确地将药物定位在胶质瘤异种移植物组织中。 AIM III将确定在小鼠异种移植模型中针对恶性神经胶质瘤的药物偶联物的功效。我们将研究EF24-FFRCK-FVIIA对该模型存活的影响，并检查药物偶联治疗的生物学相关性，包括肿瘤生长，血管生成和BBB的破坏。 公共卫生相关性：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例新病例。这些肿瘤普遍致命，患者生存期的平均长度仅为60周。该提案使用一种高度创新的方法来专门针对GBM的异常血管，以减缓其生长。尽管该提案专门针对GBM中的异常血管，但该方法可能在其他血管异常生长的疾病中发现了应用，例如糖尿病性视网膜病变，黄斑变性，子宫内膜异位症，克罗恩病，牛皮癣和其他癌症。

项目成果

Tumor angiogenesis therapy using targeted delivery of Paclitaxel to the vasculature of breast cancer metastases.

• DOI: 10.1155/2014/865732
• 发表时间: 2014
• 期刊: Journal of drug delivery
• 作者: Zhu S;Kisiel W;Lu YJ;Petersen LC;Ndungu JM;Moore TW;Parker ET;Sun A;Liotta DC;El-Rayes BF;Brat DJ;Snyder JP;Shoji M
• 通讯作者: Shoji M

Lectins identify glycan biomarkers on glioblastoma-derived cancer stem cells.

凝集素可识别胶质母细胞瘤来源的癌症干细胞上的聚糖生物标志物。

• DOI: 10.1089/scd.2011.0369
• 发表时间: 2012
• 期刊: Stem cells and development
• 影响因子: 4
• 作者: Tucker-Burden,Carol;Chappa,Prasanthi;Krishnamoorthy,Malini;Gerwe,BrianA;Scharer,ChristopherD;Heimburg-Molinaro,Jamie;Harris,Wayne;Usta,SümeyraNaz;Eilertson,CarmenD;Hadjipanayis,ConstantinosG;Stice,StevenL;Brat,DanielJ;Nash,
• 通讯作者: Nash,

Curcumin analogue UBS109 prevents bone loss in breast cancer bone metastasis mouse model: involvement in osteoblastogenesis and osteoclastogenesis.

姜黄素类似物 UBS109 可预防乳腺癌骨转移小鼠模型中的骨质流失：参与成骨细胞生成和破骨细胞生成。

• DOI: 10.1007/s00441-014-1846-4
• 发表时间: 2014
• 期刊: Cell and tissue research
• 影响因子: 3.6
• 作者: Yamaguchi,Masayoshi;Zhu,Shijun;Zhang,Shumin;Wu,Daqing;Moore,TerryM;Snyder,JamesP;Shoji,Mamoru
• 通讯作者: Shoji,Mamoru