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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（9-0二氢喹啉基）酞嗪/氢奎宁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，作为一种新的候选药物治疗b系急性淋巴细胞白血病（ALL），最常见的儿童癌症形式。在拟开展的多学科转化性研究项目中，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，进一步提高其效力，拓宽其治疗窗口。在整个项目中，生成的C-61纳米颗粒的抗白血病活性将通过体外和体内实验平台进行评估，包括定量体外细胞凋亡实验、免疫功能小鼠的小鼠bcl - 1白血病模型和人类b系ALL的SCID小鼠异种移植模型。在具体目标1中，我们将通过优化大单层脂质体囊泡的内部核心环境和内层来最大化地包裹C-61，从而开发出有效且稳定的第一代C-61纳米粒结构。在特定目标2下，我们将开发有效的第二代C-61脂质体纳米颗粒，通过用聚乙二醇修饰脂质修饰大单层脂质体囊泡的外层，改善其药效学特性。在Specific Aim 3下，我们将开发CD19定向的第三代C-61纳米颗粒，通过将抗CD19 scFv共价附着在第二代纳米颗粒的外层聚乙二醇化磷脂上。在Specific Aim 4下，我们将研究cd19特异性的第三代C-61纳米颗粒与标准化疗药物的抗白血病活性。在Specific Aim 5下，我们将研究标准抗白血病药物对cd19特异性第3代C-61纳米颗粒结构的毒性、药代动力学和疗效的影响。针对CD19-f白血病细胞syk依赖性抗凋亡存活机制的细胞型特异性纳米颗粒的开发将是克服儿童b系ALL化疗耐药的重要一步。该研究项目的成功完成可能为b系ALL（最常见的儿童癌症）的更有效和潜在的范式转变治疗策略提供基础。我们的研究将带来新的纳米技术发现，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）

Liposomal Nanoparticles of a Spleen Tyrosine Kinase P-Site Inhibitor Amplify the Potency of Low Dose Total Body Irradiation Against Aggressive B-Precursor Leukemia and Yield Superior Survival Outcomes in Mice.

脾酪氨酸激酶 P 位点抑制剂的脂质体纳米颗粒可增强低剂量全身照射对抗侵袭性 B 前体白血病的效力，并在小鼠中产生优异的生存结果。

DOI：
10.1016/j.ebiom.2015.04.005
发表时间：
2015
期刊：
EBioMedicine
影响因子：
11.1
作者：
Uckun,FatihM;Myers,DorotheaE;Cheng,Jianjun;Qazi,Sanjive
通讯作者：
Qazi,Sanjive

Targeting Mantle Cell Lymphoma with Anti-SYK Nanoparticles.

使用抗 SYK 纳米颗粒靶向套细胞淋巴瘤。

DOI：
10.6000/1927-7229.2012.01.01.1
发表时间：
2012
期刊：
Journal of analytical oncology
影响因子：
0
作者：
Cely,Ingrid;Yiv,Seang;Yin,Qian;Shahidzadeh,Anoush;Tang,Li;Cheng,Jianjun;Uckun,FatihM
通讯作者：
Uckun,FatihM

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：
10.1172/jci76610
发表时间：
2015
期刊：
The Journal of clinical investigation
影响因子：
0
作者：
Uckun,FatihM;Myers,DorotheaE;Qazi,Sanjive;Ozer,Zahide;Rose,Rebecca;D'Cruz,OsmondJ;Ma,Hong
通讯作者：
Ma,Hong

Low Dose Total Body Irradiation Combined With Recombinant CD19-Ligand × Soluble TRAIL Fusion Protein is Highly Effective Against Radiation-Resistant B-Precursor Acute Lymphoblastic Leukemia in Mice.