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

根据美国癌症协会的数据，今年将有大约25,000人死于白血病。尽管 随着治疗的不断进步，急性淋巴细胞白血病（ALL）患者仍然是高风险患者， 预后不佳。虽然一些新的治疗方式正在实施，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。这项合作工作汇集了来自 化学工程、材料科学、分子生物学、免疫学和临床医学领域， 为解决这一难题提供了一种独特的方法。初步数据提供了大量证据， 大量SH 3结构域（POSH）支架复合物的抑制导致增殖和/或细胞增殖的阻断， 在迄今为止评价的绝大多数（16例中的15例）T细胞和B细胞白血病中诱导显著的细胞凋亡。 虽然有希望，但POSH抑制剂肽治疗剂（POSHINHIB）不容易内化， 特异性靶向淋巴细胞，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- 靶向适体（Apts），细胞穿透肽（CPP）和肽两亲胶束（PAM），一种新的 可以产生能够治疗T细胞和B细胞白血病的生物材料。这一假设将在特定的 目的1通过合成Apt共轭和CPP修饰的POSHINHIB两亲胶束并对其进行表征 (Apt~A/Tat-POSHINHIBAMs）。在特异性目的2中，Apt~A/Tat-POSHINHIBAM的功能和体外特异性 将评估对常规癌症治疗剂反应不佳的T细胞和B细胞ALL的治疗。 具体目标3将包括初步实验，旨在评估体内抑制作用， Apt~A/Tat-POSHINHIBAM在小鼠异种移植模型中抗人白血病的作用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， 治疗肽。虽然高风险，但初步数据支持达特- POSHINHIB，显示了我们合成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，以创建一个复杂的交付 能够成为临床适用治疗的器械。此外，纳米颗粒的模块化性质 在这项研究中开发的所有治疗方法都可以作为一种平台技术， 治疗其他癌症以及自身免疫性疾病。

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.