Aptamer-Modified POSH Inhibitor Micelles as a Novel Leukemia Treatment Modality

适配体修饰的 POSH 抑制剂胶束作为一种新型白血病治疗方式

• 批准号: 10022329
• 负责人: MARK A. DANIELS
• 金额: $ 29.73万
• 依托单位: UNIVERSITY OF MISSOURI-COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-23 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10022329
• 关键词: Acute Lymphocytic Leukemia; Adoptive Transfer; Affect; American Cancer Society; Antineoplastic Agents; Apoptosis; Autoimmune Diseases; B-Cell Acute Lymphoblastic Leukemia; B-Cell Leukemia; B-cell precursor acute lymphoblastic leukemia cell; Basic Science; Biocompatible Materials; Biological; Biological Process; Blood; Breast; C-terminal; C10; Cancer Etiology; Cancer Relapse; Cell Line; Cells; Cessation of life; Chemical Engineering; Circular Dichroism; Clinical; Clinical Medicine; Colon; Complex; Data; Development; Devices; Diagnosis; Dose; Drug resistance; Flow Cytometry; Frequencies; Harvest; Human; Hydrophobicity; Immunology; In Vitro; Life; Lipids; Literature; Lymphocyte; Lymphoma; Lysine; Malignant Neoplasms; Micelles; Modality; Molecular Biology; Morphology; Mus; Nature; Nucleic Acids; Oncology; Ontology; Patients; Peptides; Performance; Prostate; Publishing; Reporting; Research; Resolution; SH3 Domains; Signal Pathway; Specificity; Structure; System; T-Lymphocyte; Tail; Techniques; Technology; Testing; Therapeutic; Tissues; Toxic effect; Transmission Electron Microscopy; Treatment Efficacy; Water; Work; World Health Organization; Xenograft Model; aptamer; base; childhood cancer mortality; clinical application; cytotoxicity; design; dosage; experimental study; high risk; improved; in vivo; in vivo evaluation; inhibitor/antagonist; leukemia; leukemia treatment; materials science; mixed cell culture; novel; novel anticancer drug; novel therapeutics; outcome forecast; peptide I; peptide drug; prognostic; response; scaffold; side effect; targeted delivery; therapeutic nanoparticles

According to the American Cancer Society, approximately 25,000 people will die from leukemia this year. Despite numerous treatment advances, patients with acute lymphoblastic leukemia (ALL) continue to be high-risk and have a poor prognostic outlook. While some novel therapeutic modalities are being implemented, drug resistance, cancer relapse, and off-target toxicity indicate a considerable clinical need still exists meaning safer, more efficient treatment systems must be developed. This collaborative work brings together expertise from the fields of chemical engineering, materials science, molecular biology, immunology, and clinical medicine to provide a unique approach to this difficult problem. Preliminary data provides considerable evidence that inhibition of the Plenty of SH3 Domains (POSH) scaffold complex leads to a blockade in proliferation and/or an induction in significant apoptosis in the vast majority (15 of 16) of T cell and B cell leukemias evaluated to date. While promising, the POSH inhibitor peptide therapeutic (POSHINHIB) is not readily internalized and does not specifically target lymphocytes, both of which greatly limit its bioactivity. We hypothesize that by combining cell- targeting aptamers (Apts), cell penetrating peptides (CPPs), and peptide amphiphile micelles (PAMs), a novel biomaterial can be created capable of treating T cell and B cell leukemia. This hypothesis will be tested in Specific Aim 1 by the synthesis and characterization of Apt-conjugated and CPP-modified POSHINHIB amphiphile micelles (Apt~A/Tat-POSHINHIBAMs). In Specific Aim 2, Apt~A/Tat-POSHINHIBAM function and specificity for the in vitro treatment of T cell and B cell ALL that do not respond well to conventional cancer therapeutics will be assessed. Specific Aim 3 will consist of preliminary experiments designed to evaluate the in vivo antineoplastic effects of Apt~A/Tat-POSHINHIBAM against human leukemia in a murine xenograft model. This work is expected to provide a deeper understanding into how directed delivery and biomaterials structure influence the biological efficacy of therapeutic peptides. While high risk, preliminary data support the substantial therapeutic potential of Tat- POSHINHIB, show our capacity to fabricate POSHINHIBAMs, and demonstrate Apt~A/PAMs possess enhanced selective targeting. The proposed research plan will build on these initial results to create a complex delivery device capable of becoming a clinically applicable treatment. In addition, the modular nature of the nanoparticle therapeutics developed in this research all them to serve as a platform technology that can be leveraged for the treatment of other cancers as well as autoimmune diseases.

据美国癌​​症协会称，今年约有 25,000 人将死于白血病。尽管 尽管治疗取得了许多进展，但急性淋巴细胞白血病 (ALL) 患者仍然是高风险且 预后前景不佳。虽然正在实施一些新的治疗方式，但药物 耐药性、癌症复发和脱靶毒性表明仍然存在相当大的临床需求，这意味着更安全、 必须开发更有效的处理系统。这项协作工作汇集了来自 化学工程、材料科学、分子生物学、免疫学和临床医学领域 为解决这个难题提供了独特的方法。初步数据提供了大量证据表明 抑制大量 SH3 结构域 (POSH) 支架复合物会导致增殖受阻和/或 在迄今为止评估的绝大多数（16 例中的 15 例）T 细胞和 B 细胞白血病中诱导显着凋亡。 尽管很有前景，但 POSH 抑制剂肽治疗剂 (POSSHINHIB) 不容易内化，并且不能 专门针对淋巴细胞，这两者都极大地限制了其生物活性。我们假设通过结合细胞 靶向适配体 (Apts)、细胞穿透肽 (CPP) 和肽两亲胶束 (PAM) 可以制造出能够治疗 T 细胞和 B 细胞白血病的生物材料。这个假设将在具体的测试中得到检验 目标 1：Apt 缀合和 CPP 修饰的 POSHINHIB 两亲胶束的合成和表征 （Apt~A/Tat-POSSHINHIBAM）。在特定目标 2 中，Apt~A/Tat-POSSHINHIBAM 的功能和体外特异性 将评估对传统癌症治疗反应不佳的 T 细胞和 B 细胞 ALL 的治疗。 具体目标 3 将包括旨在评估体内抗肿瘤作用的初步实验 Apt~A/Tat-POSSHINHIBAM 在小鼠异种移植模型中对抗人类白血病。这项工作预计将提供 更深入地了解定向递送和生物材料结构如何影响生物功效 治疗性肽。虽然风险较高，但初步数据支持 Tat- 的巨大治疗潜力 POSHINHIB，展示了我们制造 POSHINHIBAM 的能力，并证明 Apt~A/PAM 具有增强的 选择性瞄准。拟议的研究计划将建立在这些初步结果的基础上，以创建一个复杂的交付 能够成为临床适用治疗的设备。此外，纳米粒子的模块化性质 本研究中开发的疗法全部作为一种平台技术，可用于 治疗其他癌症以及自身免疫性疾病。