Targeting SYK Kinase in B-Lineage ALL with CD19-Specific C-61 Nanoparticles

使用 CD19 特异性 C-61 纳米颗粒靶向 B 系 ALL 中的 SYK 激酶

• 批准号: 8520251
• 负责人: FATIH M UCKUN
• 金额: $ 41.65万
• 依托单位: CHILDREN'S HOSPITAL OF LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8520251
• 关键词: Acute Lymphocytic Leukemia; Adriamycin PFS; Affect; Antibodies; Antigen-Antibody Complex; Antigens; Apoptosis; Apoptosis Promoter; Apoptotic; BCL1 Oncogene; Binding; Biodistribution; Biological Assay; Bone Marrow; Buffers; CD19 gene; CD7 gene; Cell Line; Cells; Childhood; Development; Dexamethasone; Disease-Free Survival; Dose; Drug Combinations; Drug Kinetics; Encapsulated; Environment; Epitopes; Ethylene Glycols; Evaluation; Event; Exhibits; Foundations; Generations; Goals; Homing; Human; Immune system; Immunocompetent; In Vitro; Interdisciplinary Study; Lead; Leukemic Cell; Lipids; Liposomes; Malignant Childhood Neoplasm; Malignant Neoplasms; Maximum Tolerated Dose; Mediating; Membrane; Methods; Methylprednisolone; Mission; Modeling; Monoclonal Antibodies; Mus; Nanotechnology; Particle Size; Pharmaceutical Preparations; Pharmacodynamics; Phospholipids; Phosphotransferases; Plasma; Principal Investigator; Procedures; Property; Protocols documentation; Publishing; Research; Research Project Grants; Resistance; SCID Mice; SYK gene; Side; Site; Sodium Chloride; Specificity; Spleen; Staging; Sterically Stabilized Liposome; Survival Rate; Testing; The Sun; Therapeutic; Toxic effect; Tyrosine Kinase Inhibitor; Vesicle; Vincristine; Work; Xenograft Model; Xenograft procedure; asparaginase; cell type; chemotherapy; comparative; design; drug candidate; ethylene glycol; improved; in vitro activity; in vivo; inhibitor/antagonist; leukemia; lymph nodes; monolayer; mouse model; nanoparticle; neurotensin mimic 1; novel; pH gradient; particle; programs; research study; treatment strategy; unilamellar vesicle

DESCRIPTION (provided by applicant): We recently discovered the pentapeptide mimic 1,4-Bis (9-0 dihydroquinidinyl) phthalazine / hydroquinidine 1,4-phathalazinediyl diether (C-61) as a tyrosine kinase inhibitor targeting the substrate-binding P-site of SYK as a novel drug candidate against B-lineage acute lymphoblastic leukemia (ALL), the most common form of childhood cancer. In the proposed translational multidisciplinary research project, we will prepare rationally- designed C-61 nanoparticle constructs for more effective delivery of C-61 to leukemia cells in an attempt to further improve its potency and broaden its therapeutic window. Throughout the project, the anti-leukemic activity of the generated C-61 nanoparticles will be evaluated using in vitro and in vivo assay platforms, including quantitative in vitro apoptosis assays, murine BCL-I leukemia model in immunocompetent mice, and SCID mouse xenograft models of human B-lineage ALL. Under Specific Aim 1, we will develop potent and stable liposomal 1st generation nanoparticle constructs of C-61 by optimizing the intemal core environment and inner monolayer of the large unilamellar liposomal vesicles for maximized C-61 entrapment. Under Specific Aim 2, we will develop potent 2nd generation liposomal nanoparticle constructs of C-61 with improved pharmacodynamic features by modifying the outer monolayer of the large unilamellar liposomal vesicles with poly(ethylene glycol)-modified lipids. Under Specific Aim 3, we will develop CD19- directed 3rd generation nanoparticle constructs of C-61 by incorporating anti-CD19 scFv covalently attached to PEGylated phospholipids in the outer layer of the lead 2nd generation nanoparticles. Under Specific Aim 4, we will study the anti-leukemic activity of the lead CD19-specific 3rd generation C-61 nanoparticle constructs in side by side comparison to standard chemotherapy drugs. Under Specific Aim 5, we will study the effects of standard anti-leukemia drugs on toxicity, pharmacokinetics, and efficacy of the lead CD19-specific 3rd generation C-61 nanoparticle constructs. The development of cell-type specific nanoparticles targeting SYK-dependent anti-apoptotic survival mechanism in CD19-f- leukemic cells will be a significant step forward to overcome chemotherapy resistance in childhood B-lineage ALL. The successful completion of this research project may provide the foundation for a more effective and potentially paradigm-shifting treatment strategy for B-lineage ALL, the most common form of childhood cancer. New nanotechnology discoveries that will result from our research are anticipated to significantly contribute to the mission of the NCI Alliance for Nanotechnology in Cancer.

描述（由申请人提供）：我们最近发现了五肽模拟物1，4-双（9-0二氢奎尼丁基）酞嗪/氢化奎尼丁1，4-酞嗪二基二醚（C-61）作为酪氨酸激酶抑制剂，靶向SYK的底物结合P位点，作为治疗B系急性淋巴细胞白血病（ALL）（最常见的儿童癌症形式）的新型候选药物。在拟议的转化多学科研究项目中，我们将制备合理设计的C-61纳米颗粒构建体，以更有效地将C-61递送至白血病细胞，试图进一步提高其效力并拓宽其治疗窗口。在整个项目中，将使用体外和体内试验平台评价所产生的C-61纳米颗粒的抗白血病活性，包括定量体外细胞凋亡试验、免疫活性小鼠中的小鼠BCL-I白血病模型和人B系ALL的SCID小鼠异种移植模型。在特定目标1下，我们将通过优化大单层脂质体囊泡的内核环境和内层单层来开发有效且稳定的C-61脂质体第1代纳米颗粒构建体，以最大化C-61包封。在具体目标2下，我们将通过用聚（乙二醇）修饰的脂质修饰大单层脂质体囊泡的外单层，开发具有改善药效学特征的C-61的有效第二代脂质体纳米颗粒构建体。在具体目标3下，我们将通过在第二代纳米颗粒的外层中掺入与聚乙二醇化磷脂共价连接的抗CD 19 scFv，开发C-61的CD 19定向第三代纳米颗粒构建体。在特定目标4下，我们将研究与标准化疗药物并行比较的前导CD 19特异性第三代C-61纳米颗粒构建体的抗白血病活性。在特定目标5下，我们将研究标准抗白血病药物对主要CD 19特异性第三代C-61纳米颗粒构建体的毒性、药代动力学和疗效的影响。靶向CD 19-f-白血病细胞中SYK依赖性抗凋亡存活机制的细胞类型特异性纳米颗粒的开发将是克服儿童B系ALL化疗耐药性的重要一步。这项研究项目的成功完成可能为B系ALL（最常见的儿童癌症）提供更有效和潜在的范式转移治疗策略的基础。新的纳米技术的发现，将导致从我们的研究预计将显着贡献的使命的NCI联盟纳米技术在癌症。