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：
8716686
负责人：
FATIH M UCKUN
金额：
$ 41.73万
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 2016-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8716686
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.

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，靶向底物结合 P- SYK 是一种针对 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。在拟议的转化性多学科研究项目中，我们将制备合理设计的C-61纳米颗粒结构，以更有效地将C-61递送至白血病细胞，以进一步提高其效力并拓宽其治疗窗口。在整个项目中，将使用体外和体内测定平台评估所生成的 C-61 纳米粒子的抗白血病活性，包括定量体外细胞凋亡测定、免疫活性小鼠的鼠 BCL-I 白血病模型和 SCID 小鼠异种移植模型人类 B 谱系 ALL。在具体目标 1 下，我们将通过优化大单层脂质体囊泡的内部核心环境和内部单层来开发有效且稳定的第一代 C-61 脂质体纳米颗粒结构，以最大限度地捕获 C-61。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，开发有效的第二代 C-61 脂质体纳米颗粒结构，以改善药效学特征。在具体目标 3 下，我们将通过在先导第二代纳米粒子的外层中掺入共价连接至聚乙二醇化磷脂的抗 CD19 scFv，开发 CD19 导向的 C-61 第三代纳米粒子构建体。在具体目标 4 下，我们将研究领先的 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并列比较。在具体目标 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 纳米颗粒结构的毒性、药代动力学和功效的影响。针对 CD19-f-白血病细胞中 SYK 依赖性抗凋亡生存机制的细胞类型特异性纳米粒子的开发，将是克服儿童 B 系 ALL 化疗耐药性的重要一步。该研究项目的成功完成可能为 B 系 ALL（最常见的儿童癌症形式）的更有效且可能改变范式的治疗策略奠定基础。我们的研究产生的新纳米技术发现预计将为 NCI 癌症纳米技术联盟的使命做出重大贡献。

项目成果

期刊论文数量（27）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Recombinant human CD19L-sTRAIL effectively targets B cell precursor acute lymphoblastic leukemia.

重组人 CD19L-sTRAIL 有效靶向 B 细胞前体急性淋巴细胞白血病。

DOI：
发表时间：
2015-03-02
期刊：
影响因子：
0
作者：
Uckun, Fatih M;Myers, Dorothea E;Qazi, Sanjive;Ozer, Zahide;Rose, Rebecca;D'Cruz, Osmond J;Ma, Hong
通讯作者：
Ma, Hong

Constitutive function of the Ikaros transcription factor in primary leukemia cells from pediatric newly diagnosed high-risk and relapsed B-precursor ALL patients.

新诊断的高危和复发 B 前体 ALL 儿童原发性白血病细胞中 Ikaros 转录因子的组成功能。

DOI：
发表时间：
2013
期刊：
影响因子：
3.7
作者：
Uckun, Fatih M;Ma, Hong;Ishkhanian, Rita;Arellano, Martha;Shahidzadeh, Anoush;Termuhlen, Amanda;Gaynon, Paul S;Qazi, Sanjive
通讯作者：
Qazi, Sanjive

ERBB1/EGFR and JAK3 Tyrosine Kinases as Potential Therapeutic Targets in High-Risk Multiple Myeloma.

ERBB1/EGFR 和 JAK3 酪氨酸激酶作为高风险多发性骨髓瘤的潜在治疗靶点。