Enzyme-instructed self-assembly for anticancer nanomedicine

描述（由申请人提供）：癌症是恶性细胞不受控制的生长和扩散，几乎可以影响身体的任何组织，仍然是公共卫生的主要负担。抗癌化疗是最重要的辅助治疗方法，但如何对肿瘤组织或器官进行靶向有效治疗仍是化疗的一大挑战。这项工作将开发用于控制细胞行为和命运的小分子分子纳米纤维。这项工作的目标是探索细胞对酶引导的分子纳米纤维形成的反应，并最终开发出针对癌细胞的新型纳米药物。这个应用程序是由假设和设计驱动的。我们推测，酶引导的分子自组装作为一种独特的分子纳米纤维制造方法，可以调节细胞外和细胞内的微环境，并选择性地导致癌细胞死亡。为了验证这一假设，我们将设计在细胞外或细胞内酶的作用下自组装形成纳米纤维的分子，表征纳米纤维的物理化学性质，并评估分子纳米纤维在体外和体内形成的生物学特性和影响。具体来说，这项拟议的研究将(i)设计和合成可以通过酶催化转化为分子纳米纤维的底物；（ii）表征所设计前驱体的酶催化反应以及相应分子纳米纤维的行为和性质；（iii）在体外评估分子纳米纤维对代表性癌细胞系的活性；(4)利用动物模型研究分子纳米纤维在体内的形成和抗癌作用。这项研究将为制造合成纳米结构作为靶向癌细胞的纳米药物提供一个新的平台。我们期望这种新方法将提高对癌症治疗的基本理解，为设计纳米级抗癌药物提供指导原则，并最终导致基于分子自组装和酶催化整合的癌症治疗新范式。

DESCRIPTION (provided by applicant): Cancer, the uncontrolled growth and spread of malignant cells that can affect almost any tissue of the body, continues to be a major burden to public health. Anticancer chemotherapy is the most important adjuvant therapy, but the targeted and effective therapy to the tumorous tissues or organs, however, remains as a significant challenge in chemotherapy. The proposed work will develop molecular nanofibers of small molecules for controlling the behavior and the fate of cells. The goal of this work is to explore cellular responses to enzyme-instructed formation of molecular nanofibers and eventually develop new nanomedicines to target cancer cells. This application is both hypothesis and design driven. We hypothesize that enzyme- instructed molecular self-assembly, as a unique way to create molecular nanofibers, can modulate extra- and intracellular microenvironment and selectively lead to death of cancer cells. To validate the hypothesis, we will design molecules that self-assemble to form nanofibers upon the action of extra- or intracellular enzyme(s), characterize the physiochemical properties of the nanofibers, and assess the biological properties and effects of the formation of molecular nanofibers in vitro and in vivo. Specifically, this proposed research will (i) design and synthesize substrates that can be converted into molecular nanofibers by enzyme catalysis; (ii) characterize the enzyme-catalyzed reactions of the designed precursors and the behavior and properties of the corresponding molecular nanofibers; (iii) evaluate the activity of the molecular nanofibers against representative cancer cell lines in vitro; and (iv) examine formation and anticancer effects of the molecular nanofibers in vivo using animal models. This research will potentially provide a new platform for creating synthetic nanostructures as nanomedicine to target cancer cells. We anticipate that this new approach will improve fundamental understanding of cancer therapy, provide guiding principles to design anticancer agents at nanoscale, and ultimately lead to a new paradigm of cancer therapy that are based on the integration of molecular self-assembly and enzyme catalysis. PUBLIC HEALTH RELEVANCE: The overall goal of this work is to develop a novel approach for creating nanomedicine to target cancer cells. Using enzyme to instruct the formation of synthetic nanostructures, this approach will ultimately lead to a new paradigm of cancer therapy for improving health and quality of life for the millions of people who will need anticancer treatment in the future.