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

摘要 转移性骨肉瘤（mOS）的治疗效果仍然不佳，并且多年来没有改善 四个十年。因此，迫切需要开发治疗 mOS 的新方法。我们意外地发现 酶指导自组装 (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旨在测试原位形成的 NF 抑制小鼠模型中的肿瘤生长。该研究计划将重点关注两个具体目标：目标 1， mOS 细胞核中 EISA 分子的合成和表征；目标 2，试点研究 用于在临床相关小鼠模型中抑制 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) 我们的初步结果显示 EISA 在细胞核内形成 NF 来选择性抑制 mOS 细胞，并且 (iii) EISA 形成胞质 NF 来选择性抑制 mOS 细胞 选择性地抑制体内mOS肿瘤。这项创新是通过 EISA 靶向 mOS 细胞的细胞核。的 拟议研究的成功将有助于开发新的分子靶向剂 选择性地杀死mOS，这可能最终导致治疗mOS的突破。

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.