Subcellular enzyme-instructed self-assembly for molecular anticancer nanomedicines

摘要 尽管在分子治疗和免疫治疗方面取得了进展，但多种潜在的细胞机制仍然存在。 导致对癌症治疗的抵抗。迫切需要制定创新的办法来满足这些需求。 挑战本研究旨在开发亚细胞酶指导自组装（sEISA）， 包括线粒体EISA（mitoEISA）和细胞质EISA（cytoEISA），用于产生分子纳米纤维 以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选择性地靶向癌细胞的线粒体，并最大限度地减少耐药性。最重要的是， 我们的初步研究表明，sEISA抑制体内免疫抑制肿瘤的生长。因此我们 建议进一步开发针对耐药癌细胞和肿瘤的sEISA。拟议的研究已 三个具体目标：目标1，开发选择性靶向癌细胞的mitoEISA;目标2，开发 cytoEISA用于最小化耐药性和免疫抑制;目的3，评估卵巢癌患者的sEISA 癌症异种移植鼠模型。中心假设是sEISA时空产生分子 纳米纤维，与多种细胞蛋白相互作用，中断癌症内部的多种细胞过程 细胞，以尽量减少耐药性。我们的初步结果支持中心假设。创新之处在于 分子纳米纤维的作用机制明显偏离了配体-受体法则， 目前的抗癌药物。拟议工作的长期目标是开发sEISA，以产生分子 纳米纤维用于克服癌症治疗中的抗性。我们预计，这项研究将提供创新的 抗癌方法为了解决癌症治疗中的耐药性和免疫抑制问题， 从而最终提高癌症患者的生存率。

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.