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.

项目概要 该提案的长期目标是设计、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治疗大颗粒淋巴细胞的研究 （LGL）白血病。 LGL 白血病由 T 细胞或自然杀伤细胞 (NK) 的克隆增殖引起 细胞。 LGL 白血病患者尚无已知的治疗方法。白血病LGL具有耐药性 Fas 诱导的细胞凋亡并表现出高水平的活化 STAT3，这是致癌的关键介质 发信号。白血病 LGL 中 STAT3 的抑制会导致存活蛋白 Mcl-1 的减少和 对 Fas 介导的细胞凋亡的敏感性增加。 该提案的基础是第一代 C6-神经酰胺纳米脂质体，该纳米脂质体已被 被国家纳米技术表征实验室采用为平台技术 癌症研究所。具体目标集中在纳米级、非 聚集 C6-神经酰胺脂质体提供极其灵敏、选择性、无毒、隐形、 用于系统靶向疏水性化疗药物的可生物降解和响应平台 和/或针对LGL白血病细胞的siRNA。多功能的潜在临床用途 纳米脂质体，旨在传递细胞可渗透的神经酰胺类似物（C6 神经酰胺）以及 目标特异性 siRNA 和/或甲氨蝶呤，将在 LGL 白血病 Fischer F344 大鼠模型中进行测试。 据推测，甲氨蝶呤和/或 siRNA 在掺入神经酰胺的细胞中同时递送 脂质体对LGL白血病具有协同疗效。 第一个具体目标将检验脂质体短链系统递送的假设 神经酰胺在已建立的动物模型中抑制 LGL 白血病。具体目标 2 将检验假设 聚乙二醇化阳离子脂质体可以递送抑制性 siRNA 和化疗药物 体外和体内进入LGL白血病细胞，从而增强其抗白血病活性。具体的 目标 3 将检验以下假设：单克隆抗体与 CD8（CD8 的特异性标记）结合。 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 中的实验是免疫脂质体递送的重要原理验证研究 通过靶向癌细胞上表达的表面抗原。第二代的开发 该提案中概述的癌症纳米技术平台具有改善癌症的潜力 疗法。 。项目叙述 该提案的目标是使用以下药物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。我们建议全身靶向 C6-神经酰胺 将甲氨蝶呤和 siRNA 封装到已建立的阳离子纳米免疫脂质体制剂中 LGL白血病动物模型。这些研究将为利用这种疗法提供基础 方法对患有这种不治之症的人类受试者进行治疗。