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(申请人提供)：我们最近发现了五肽模拟1，4-二(9-0二氢奎宁)二氮杂氮/氢奎宁1，4-二氮杂二醚(C-61)作为一种酪氨酸激酶抑制剂，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)的新候选药物，B系急性淋巴细胞白血病(ALL)是最常见的儿童癌症。在拟议的翻译多学科研究项目中，我们将制备设计合理的C-61纳米颗粒结构，以便更有效地将C-61输送到白血病细胞，试图进一步提高其效力，拓宽其治疗窗口。在整个项目中，将使用体外和体内测试平台来评估生成的C-61纳米粒子的抗白血病活性，包括体外细胞凋亡定量分析、免疫活性小鼠中的小鼠bclI白血病模型以及人类B系ALL的SCID小鼠异种移植模型。在具体目标1下，我们将通过优化大的单层脂质体囊泡的内部核心环境和内部单层来最大限度地提高C-61的包封率，开发有效和稳定的C-61脂质体第一代纳米结构。在具体目标2下，我们将通过用聚乙二醇改性的脂类修饰大单层脂质体的外层来开发具有改善药效学特性的有效的第二代脂质体纳米颗粒C-61。在具体目标3下，我们将通过将抗CD19单链抗体共价连接到聚乙二醇化磷脂的外层来开发CD19导向的C-61第三代纳米颗粒结构。在特定目标4下，我们将研究先导CD19特异性第三代C-61纳米颗粒结构的抗白血病活性，并与标准化疗药物进行比较。在特定目标5下，我们将研究标准抗白血病药物对先导CD19特异性第三代C-61纳米粒构建物的毒性、药代动力学和疗效的影响。针对CD19-f-白血病细胞中SYK依赖的抗凋亡生存机制的细胞类型特异性纳米粒的开发将是克服儿童B系ALL化疗耐药的重要一步。这项研究项目的成功完成可能会为B系ALL这一最常见的儿童癌症的更有效和潜在的范式转换治疗策略提供基础。我们的研究将产生新的纳米技术发现，预计将对NCI癌症纳米技术联盟的使命做出重大贡献。