Testing in-situ formed nanofibers for inhibiting metastatic osteosarcoma (mOS) in murine models

在小鼠模型中测试原位形成的纳米纤维抑制转移性骨肉瘤（mOS）的效果

• 批准号: 10448284
• 负责人: Bing Xu
• 金额: $ 8.13万
• 依托单位: BRANDEIS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-09 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10448284
• 关键词: Alkaline Phosphatase; Animal Model; Bone neoplasms; Cell Culture Techniques; Cell Nucleus; Cells; Cellular Assay; Coculture Techniques; Development; Disease; Enzymes; Image; In Situ; Lead; Lung; Metastatic Osteosarcoma; Molecular; Molecular Target; NMR Spectroscopy; Nanotechnology; Patient-Focused Outcomes; Peptide Synthesis; Peptides; Phase; Pilot Projects; Prognosis; Reaction; Research; Services; Solid; Structure; Testing; Therapeutic; Treatment outcome; anti-cancer; anti-cancer therapeutic; cancer therapy; clinically relevant; design; enzyme activity; improved; improved outcome; in vivo; innovation; mouse model; nanofiber; nanofibrillar; new therapeutic target; novel strategies; osteosarcoma; overexpression; primary bone cancer; programs; self assembly; small molecule; success; targeted agent; tumor; tumor growth

Abstract The treatment outcome of metastatic osteosarcoma (mOS) remains poor and has not improved for over four decades. Thus, developing novel approaches for treating mOS is urgently needed. We unexpectedly find that enzyme-instructed self-assembly (EISA) is able to form nanofibers (NFs) inside the nuclei of mOS cells and selectively killing the mOS cells in cell culture. This proposed pilot study is to test the in-situ formed NFs for inhibiting tumor growth in murine models. This research program will focus on two specific aims: Aim 1, synthesis and characterization of the molecules for EISA in the nuclei of mOS cells; Aim 2, pilot study of the EISA substrates for inhibiting mOS tumors in clinically relevant murine models. The rigor of prior research is that (i) overexpression of alkaline phosphatase (ALP) is a key feature of mOS, (ii) our preliminary results show that EISA forms NFs inside nuclei to selectively inhibit mOS cells, and (iii) EISA forms cytosolic NFs to selectively inhibit mOS tumors in vivo. The innovation is to target the nuclei of mOS cells by EISA. The success of the proposed studies will contribute to the development of new molecular targeting agents for selectively killing mOS, which may ultimately lead to breakthrough in treating mOS.

摘要 转移性骨肉瘤（mOS）的治疗结果仍然很差， 四十年了因此，迫切需要开发用于治疗mOS的新方法。我们意外地发现， 酶指导的自组装（EISA）能够在mOS细胞的细胞核内形成纳米纤维（NF）， 选择性杀死细胞培养物中的mOS细胞。这项拟议的试点研究是为了测试原位形成的NF， 在小鼠模型中抑制肿瘤生长。这项研究计划将侧重于两个具体目标：目标1， 在mOS细胞核中用于EISA的分子的合成和表征;目的2， 用于在临床相关鼠模型中抑制mOS肿瘤的EISA底物。先前研究的严谨性在于， (i)碱性磷酸酶（ALP）的过度表达是mOS的一个关键特征，（ii）我们的初步结果表明， EISA在细胞核内形成NF以选择性地抑制mOS细胞，和（iii）EISA形成胞质NF以 选择性抑制体内mOS肿瘤。创新点在于通过EISA靶向mOS细胞的细胞核。的 这些研究的成功将有助于开发新的分子靶向药物， 选择性杀死mOS，这可能最终导致治疗mOS的突破。