Targeted Therapeutics of LGL Leukemia utilizing Ceramide Nanoliposomes

利用神经酰胺纳米脂质体靶向治疗 LGL 白血病

• 批准号: 7847066
• 负责人: Thomas Patrick Loughran
• 金额: $ 1.75万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-01 至 2010-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7847066
• 关键词: Adopted; Animal Model; Antisense Oligonucleotides; Apoptosis; Apoptotic; CD8B1 gene; Cells; Ceramides; Clinical; Data; Development; Disease; Dose; Drug Delivery Systems; Drug Formulations; Encapsulated; Foundations; Generations; Goals; Immunoliposome; In Vitro; Inbred F344 Rats; Laboratories; Large granular lymphocyte; Leukemic Cell; Licensing; Lipids; Liposomes; MCL1 protein; Malignant Neoplasms; Mediating; Mediator of activation protein; Medicine; Methods; Methotrexate; Modeling; Molecular; Monoclonal Antibodies; N-caproylsphingosine; Nanotechnology; National Cancer Institute; Natural Killer Cells; Oncogenic; Pathogenesis; Pathway interactions; Patients; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Play; Research; Research Personnel; Resistance; Role; STAT3 gene; Second Messenger Systems; Signal Transduction; Small Interfering RNA; Surface Antigens; T-Lymphocyte; Technology; Testing; Therapeutic; Toxicology; analog; base; cancer cell; chronic T-cell leukemia; college; combinatorial; design; human subject; improved; in vivo; innovation; killings; nanoscale; next generation; novel; novel strategies; research study; second messenger; stability testing; therapeutic target; therapy development; tumor

Project Summary The broad long term goal of this proposal is to design, develop and optimize the next-generation of pegylated C6-ceramide cationic liposomal formulations for treatment of large granular lymphocyte (LGL) leukemia. LGL leukemia arises from clonal proliferation of either T cells or natural killer (NK) cells. There is no known curative therapy for patients with LGL leukemia. Leukemic LGL are resistant to Fas-induced apoptosis and display high levels of activated STAT3, a critical mediator of oncogenic signaling. Inhibition of STAT3 in leukemic LGL causes a decrease in survival protein Mcl-1 and an increased sensitivity to Fas-mediated apoptosis. The foundation of this proposal is a first generation C6-ceramide nanoliposome which has been adopted as platform technology by the Nanotechnology Characterization Laboratory of the National Cancer Institute. The specific aims are focused around the central hypothesis that nano-scale, non- aggregating C6-ceramide liposomes offer exquisitely sensitive, selective, non-toxic, stealthy, biodegradable and responsive platforms for systemically targeting hydrophobic chemotherapeutic drugs and/or siRNA to LGL leukemic cells. The potential clinical usefulness of multi-functional nanoliposomes, designed to deliver cell-permeable analogs of ceramide (C6 ceramide) as well as target-specific siRNA and/or Methotrexate, will be tested in a Fischer F344 rat model of LGL leukemia. It is hypothesized that simultaneous delivery of Methotrexate and/or siRNA in a ceramide-incorporated liposome will have synergistic efficacy in LGL leukemia. The first specific Aim will test the hypothesis that systemic delivery of liposomal short-chain ceramide inhibits LGL leukemia in an established animal model. Specific Aim 2 will test the hypothesis that the pegylated cationic liposomes allow delivery of inhibitory siRNA and chemotherapeutic drugs into LGL leukemic cells in vitro and in vivo, such that their anti-leukemic activity is enhanced. Specific Aim 3 will test the hypothesis that conjugation of a monoclonal antibody to CD8, the specific marker for LGL leukemia, will ¿target¿ the therapeutic liposomes to LGL leukemic cells in vitro and in vivo. Experiments in specific aim 3 are important proof-of-principle studies for delivery of immunoliposomes by targeting surface antigens expressed on cancer cells. Development of this second generation cancer nanotechnology platform as outlined in this proposal has potential for improved cancer therapeutics. . Project Narrative The goal of this proposal is to develop therapy for large granular lymphocyte (LGL) leukemia using a novel cancer nanotechnology platform. We propose to administer systemically targeted C6-ceramide cationic nanoimmunoliposome formulations encapsulating methotrexate and siRNAs to an established animal model of LGL leukemia. These studies will provide the foundation for utilizing this therapeutic approach in human subjects with this incurable disease.

项目摘要 该提案的广泛长期目标是设计、开发和优化下一代 聚乙二醇化C6-神经酰胺阳离子脂质体制剂用于治疗大颗粒淋巴细胞 (LGL)白血病LGL白血病由T细胞或自然杀伤细胞（NK）的克隆性增殖引起 细胞对于LGL白血病患者没有已知的治愈性疗法。白血病LGL耐药 Fas诱导的细胞凋亡，并显示高水平的活化的STAT 3，一个致癌的关键介质， 发信号。抑制白血病LGL中的STAT 3导致存活蛋白Mcl-1的减少， 增加对Fas介导的凋亡的敏感性。 该提议的基础是第一代C6-神经酰胺纳米脂质体， 作为平台技术被国家纳米技术表征实验室采用 癌症研究所.具体的目标是围绕中心假设，即纳米尺度，非- 聚集的C6-神经酰胺脂质体提供了灵敏、选择性、无毒、隐蔽 用于全身靶向疏水性化疗药物的生物可降解和响应性平台 和/或siRNA。多功能的潜在临床用途 纳米脂质体，设计用于递送神经酰胺（C6神经酰胺）的细胞可渗透类似物以及 将在LGL白血病的Fischer F344大鼠模型中测试靶特异性siRNA和/或甲氨蝶呤。 假设在并入有神经酰胺的微囊中同时递送甲氨蝶呤和/或siRNA是有效的。 脂质体在LGL白血病中具有协同功效。 第一个具体目标将检验脂质体短链的全身递送 神经酰胺在建立的动物模型中抑制LGL白血病。具体目标2将检验假设 聚乙二醇化的阳离子脂质体允许递送抑制性siRNA和化疗药物 在体外和体内导入LGL白血病细胞，从而增强其抗白血病活性。具体 目的3将检验单克隆抗体与CD 8（CD 8的特异性标志物）缀合的假设， LGL白血病，将在体外和体内将治疗性脂质体靶向LGL白血病细胞。 具体目标3中的实验是用于递送免疫脂质体的重要原理验证研究 通过靶向癌细胞上表达的表面抗原。第二代的发展 该提案中概述的癌症纳米技术平台具有改善癌症的潜力 治疗学 .项目叙述 该提案的目标是开发大颗粒淋巴细胞（LGL）白血病的治疗方法， 新型癌症纳米技术平台。我们建议给予全身靶向C6-神经酰胺 阳离子纳米免疫脂质体制剂包封甲氨蝶呤和siRNA， LGL白血病动物模型。这些研究将为利用这种治疗方法提供基础 在患有这种不治之症的人类受试者身上的方法。