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

基本信息

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
项目类别：
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

项目摘要

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.

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淋巴细胞白血病（全部），这是儿童癌最常见的形式。在拟议的翻译多学科研究项目中，我们将准备合理设计的C-61纳米颗粒构建体，以更有效地将C-61传递到白血病细胞，以试图进一步提高其效力并扩大其治疗窗口。在整个项目中，将使用体外和体内测定平台评估所产生的C-61纳米颗粒的抗白血病活性，包括体外凋亡测定法，免疫能力小鼠中的鼠BCL-I白血病模型，以及人类B-Lineage人类B-Lineage的Scid小鼠Xenograft模型。在特定的目标1下，我们将通过优化大型Unilamellar脂质体囊泡的Intemal Core环境和内部单层来开发C-61的有效且稳定的脂质体1代纳米颗粒构建体，以最大程度地提高C-61的含量。在特定的目标2下，我们将通过用聚（乙烯甘油）改性的脂质修饰大型单层脂质体囊泡的外部单层，从而开发具有C-61的有效的C-61的脂质体纳米颗粒构建体，具有改进的药效学特征。在特定的目标3下，我们将通过在铅第二代纳米颗粒的外层中共同结合与卵磷酸化的磷脂的共同结合，将C-61的CD19定向第三代纳米颗粒构建体。在特定目标4下，我们将研究铅CD19特异性第三代C-61纳米颗粒构建体的抗白血病活性与标准化疗药物并排比较。在特定目标5下，我们将研究标准抗白血病药物对铅CD19特异性第三代C-61纳米粒子构建体的毒性，药代动力学和功效的影响。 CD19-F-白细胞细胞中靶向SYK依赖性抗凋亡生存机制的细胞类型特异性纳米颗粒的发展将是克服儿童B-Linege的化学疗法耐药性的重要一步。该研究项目的成功完成可能为B-Linege All（最常见的儿童癌症形式）制定了更有效且潜在的范式转移治疗策略的基础。预计我们的研究将导致的新纳米技术发现将显着促进NCI纳米技术在癌症中的使命。