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

根据美国癌症协会的数据，今年大约有2.5万人死于白血病。尽管 许多治疗进展，急性淋巴细胞白血病(ALL)患者仍然是高危和 预测前景不佳。在一些新的治疗方式正在实施的同时，药物 耐药性、癌症复发和靶外毒性表明仍有相当大的临床需求，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、免疫学和临床医学等领域 为这一难题提供了一种独特的方法。初步数据提供了相当多的证据 抑制大量SH3结构域(POSH)支架复合体导致抑制增殖和/或 到目前为止，对绝大多数(15/16)的T细胞和B细胞白血病的诱导明显的细胞凋亡进行了评估。 尽管前景看好，但POSH抑制肽疗法(POSHINHIB)并不容易内化，也不 专门针对淋巴细胞，这两种细胞都极大地限制了其生物活性。我们假设通过结合细胞- 一种新型的靶向适体(Apts)、细胞穿透肽(CPPs)和多肽两亲性胶束(PAMS) 可以创造出能够治疗T细胞和B细胞白血病的生物材料。这一假设将在具体情况下得到检验 目的1通过APT共轭和CPP修饰的POSHINHIB两亲性胶束的合成与表征 (APT~A/TAT-POSHINHIBAMS)。在特异性靶点2，APT~A/TAT-POSHINHIBAM的体外功能和特异性 对所有对传统癌症疗法反应不佳的T细胞和B细胞的治疗将进行评估。 具体目标3将包括初步实验，旨在评估在体内的抗肿瘤作用 APT~A/TAT-POSHINHIBAM在小鼠异种移植模型中抗人白血病的研究这项工作有望提供 更深入地了解定向给药和生物材料结构对生物有效性的影响 治疗性多肽。虽然风险很高，但初步数据支持TAT的巨大治疗潜力-- POSHINHIB，展示我们制造POSHINHIBAM的能力，并展示APT~A/PAM具有增强的 有选择地瞄准。拟议的研究计划将以这些初步结果为基础，创建复杂的交付 能够成为临床适用的治疗方法的装置。此外，纳米颗粒的模块化性质 治疗公司在这项研究中开发的所有这些技术都是作为一种平台技术，可以利用 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.