Subcellular Enzyme-instructed self-assembly for molecular anticancer nanomedicines

摘要 尽管分子治疗和免疫治疗取得了进展，但多种潜在的细胞机制 导致对癌症治疗的抵抗。迫切需要开发创新的方法来满足这些要求 挑战。建议的研究是发展亚细胞酶指导的自组装(SEISA)，它 包括线粒体EISA(MitoEISA)和细胞质EISA(CytoEISA)，用于生成分子纳米纤维 克服癌症治疗中的耐药性和免疫抑制。我们的初步研究表明 SEISA选择性地针对癌细胞的线粒体，将耐药性降至最低。最重要的是， 我们的初步研究表明，SEISA在体内抑制免疫抑制肿瘤的生长。因此，我们 建议进一步开发抗耐药癌细胞和肿瘤的SEISA。拟议中的研究已经 三个具体目标：目标1，开发用于选择性靶向癌细胞的mitoEISA；目标2，开发 用于最小化耐药性和免疫抑制的细胞EISA；以及目标3，评估卵巢中的SEISA 肿瘤异种移植小鼠模型。中心假设是SEISA时空生成分子 纳米纤维，它与多种细胞蛋白相互作用，干扰癌症内的多种细胞过程 细胞将抗药性降到最低。我们的初步结果支持中心假说。创新之处在于 分子纳米纤维的作用机制明显偏离了配体-受体的教条。 目前的抗癌药物。这项拟议工作的长期目标是开发SEISA来产生分子 用于克服癌症治疗中的耐药性的纳米纤维。我们期待这项研究将提供创新的 抗癌方法解决癌症治疗中的耐药性和免疫抑制问题， 从而最终将提高癌症患者的存活率。

ABSTRACT Despite the progress in molecular therapy and immunotherapy, multiple underlying cellular mechanisms cause resistance to cancer therapy. There are urgent needs to develop innovative approaches to meet these challenges. The proposed study is to develop subcellular enzyme-instructed self-assembly (sEISA), which includes mitochondrial EISA (mitoEISA) and cytoplasmic EISA (cytoEISA), for generating molecular nanofibers to overcome drug resistance and immunosuppression in cancer therapy. Our preliminary studies have shown that sEISA selectively targets the mitochondria of cancer cells and minimizes drug resistance. Most importantly, our preliminary study shows that sEISA inhibits the growth of immunosuppressive tumors in vivo. Thus, we propose to further develop sEISA against drug resistant cancer cells and tumors. The proposed research has three specific aims: Aim 1, developing mitoEISA for selectively targeting cancer cells; Aim 2, developing cytoEISA for minimizing drug resistance and immunosuppression; and Aim 3, evaluating sEISA in ovarian cancer xenograft murine models. The central hypothesis is that sEISA spatiotemporally generates molecular nanofibers, which interact with multiple cellular proteins and interrupt multiple cellular processes inside cancer cells to minimize drug resistance. Our preliminary results support the central hypothesis. The innovation is that the mechanisms of the action of the molecular nanofibers significantly depart from the ligand-receptor dogma of the current anticancer drugs. The long-term goal of the proposed work is to develop sEISA to generate molecular nanofibers for overcoming resistance in cancer therapy. We anticipate that this research will provide innovative anticancer approaches to address the problems of drug resistance and immunosuppression in cancer therapy, thus ultimately will improve the survivorship of cancer patients.