Enzyme-instructed self-assembly for molecular anticancer nanomedicines

 描述（由申请人提供）：癌症是公共卫生的主要负担。抗癌化疗仍然是手术最重要的辅助治疗，但多种潜在的细胞机制使治疗复杂化。即使治疗最初有效，基因组的不稳定性也会导致耐药性的出现，这是化疗中最重要的挑战。我们之前的研究表明，由无害单体（例如，D-肽）在体外和体内选择性抑制癌细胞的生长。这一发现预示着新的抗癌药物，强大的目标癌细胞，而不伤害正常细胞。特别地，酶指导的分子纳米纤维抑制几种耐药癌细胞（例如，MES-SA/Dx 5、SKOV 3和A2780 cis）通过与主要基于配体-受体相互作用的常规抗癌药物的机制根本不同的机制。因此，我们建议探索酶指导的D-肽分子纳米纤维作为克服癌症耐药性的范式转变方法。这项研究的中心假设是，由酶促反应时空定义的D-肽的分子纳米纤维与多种细胞蛋白相互作用并中断多种细胞过程以抑制药物敏感性和耐药性癌细胞。这项工作的目标是阐明D肽分子纳米纤维的酶指导形成如何抑制癌细胞，并最终开发新的纳米药物来靶向耐药癌细胞而不伤害正常细胞。具体而言，这项拟议的研究将（i）设计和合成D-肽用于酶指导的自组装以形成分子纳米纤维（即，酶指导的分子纳米纤维）;（ii）评估D-肽的酶指导的分子纳米纤维对抗细胞培养物中的耐药癌细胞的活性;（iii）鉴定D-肽的分子纳米纤维的细胞位置和蛋白质靶点，并揭示由D-肽的分子纳米纤维扰动的细胞过程;和（iv）在卵巢癌小鼠模型中评价D-肽的酶指导的分子纳米纤维对抗耐药癌细胞的活性。这项研究探索了一种未被探索的分子实体D-肽的自组装，从而为基于酶反应（而不是酶抑制）的纳米医学提供了一个新的平台。我们预计，这种新方法将提供新分子、新技术和前所未有的范例，最终提高癌症患者的生存率。

 DESCRIPTION (provided by applicant): Cancer is a major burden to public health. Anticancer chemotherapy continues to be the most important adjuvant therapy to surgery, but multiple underlying cellular mechanisms complicate the treatment. Even when the treatment is initially effective, genomic instability causes the emergence of drug resistance, which is the most significant challenge in chemotherapy. Our previous research has shown that molecular nanofibers, formed by the self-assembly of innocuous monomers (e.g., D-peptides), selectively inhibit the growth of cancer cells in vitro and in vivo. This discovery promises novel anticancer agents that robustly target cancer cells while sparing normal cells. Particularly, enzyme-instructed molecular nanofibers inhibit several drug-resistant cancer cells (e.g., MES-SA/Dx5, SKOV3, and A2780cis) by mechanisms that differ fundamentally from those of conventional anticancer drugs that largely are based on ligand-receptor interactions. Thus, we propose to explore the enzyme-instructed molecular nanofibers of D-peptides as a paradigm-shifting approach that overcomes drug resistance in cancer. The central hypothesis of this research is that molecular nanofibers of D- peptides, spatiotemporally defined by enzymatic reactions, interact with multiple cellular proteins and interrupt multiple cellular processes to inhibit both drug sensitive and resistant cancer cells. The goal of this work is to elucidate how enzyme-instructed formation of molecular nanofibers of D-peptides inhibits cancer cells and ultimately to develop new nanomedicines to target drug-resistant cancer cells without harming normal cells. Specifically, this proposed research will (i) design and synthesize D-peptides for enzyme-instructed self- assembly to form molecular nanofibers (i.e., enzyme-instructed molecular nanofibers); (ii) evaluate the activity of the enzyme-instructed molecular nanofibers of D-peptides against drug-resistant cancer cells in cell culture;; (iii) identify the cellular location and protein targets of the molecular nanofibers of D-peptides and reveal the cellular processes perturbed by the molecular nanofibers of D-peptides; and (iv) evaluate the activity of the enzyme-instructed molecular nanofibers of D-peptides against drug-resistant cancer cells in ovarian cancer mouse models. This research explores the self-assembly of an underexplored molecular entity, D-peptides, thus providing a new platform for nanomedicine, based on enzyme reactions (rather than enzyme inhibition). We anticipate that this new approach will provide new molecules, novel technologies, and an unprecedented paradigm that will ultimately improve the survivorship of cancer patients.