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Enzyme-instructed self-assembly for anticancer nanomedicine

用于抗癌纳米药物的酶指导自组装

基本信息

批准号：
8442195
负责人：
Bing Xu
金额：
$ 29.89万
依托单位：
BRANDEIS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-02-08 至 2015-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8442195
关键词：
Adjuvant Therapy Affect Animal Model Antineoplastic Agents Area Bacteria Behavior Behavior Control Biochemical Biological Biology Cancer Death Rates Cancer cell line Catalysis Cell Death Cell physiology Cells Cessation of life Complex Death Rate Diagnostic Drug Delivery Systems Effectiveness Environment Enzymes Focal Adhesions Foundations Future Generations Goals Growth Health In Vitro Incidence Individual Invaded Knowledge Lead Ligands Location Malignant Neoplasms Malignant neoplasm of esophagus Malignant neoplasm of liver Malignant neoplasm of pancreas Microfilaments Modality Molecular Multi-Drug Resistance Nanostructures Nanotechnology Normal Cell Organ Play Process Property Public Health Quality of life Reaction Research Role Specificity Testing Therapeutic Tissues Toxic effect Treatment Protocols United States Work anticancer treatment base biological systems biomaterial compatibility cancer cell cancer therapy cell behavior chemotherapy design effective therapy enzyme substrate extracellular frontier improved in vivo interest killings macromolecule molecular assembly/self assembly mortality nanofiber nanomedicine nanoscale nanoscience novel novel diagnostics novel strategies public health relevance rapid growth receptor binding response self assembly small molecule statistics tumor

项目摘要

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.

描述(申请人提供)：癌症，恶性细胞的不受控制的生长和扩散，几乎可以影响到身体的任何组织，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手段，但针对肿瘤组织或器官的靶向有效治疗仍是化疗领域的一大挑战。这项拟议的工作将开发小分子分子纳米纤维，用于控制细胞的行为和命运。这项工作的目标是探索细胞对酶指令形成分子纳米纤维的反应，并最终开发针对癌细胞的新纳米药物。这个应用既是假设的，也是设计驱动的。我们假设，酶引导的分子自组装作为产生分子纳米纤维的独特方式，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(S)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。具体地说，这项拟议的研究将(I)设计和合成可通过酶催化转化为分子纳米纤维的底物；(Ii)表征所设计的前体的酶催化反应以及相应的分子纳米纤维的行为和性质；(Iii)评估分子纳米纤维对具有代表性的癌细胞的体外活性；以及(Iv)通过动物模型检测分子纳米纤维的体内形成和抗癌效果。这项研究可能会为创造合成纳米结构作为针对癌细胞的纳米药物提供一个新的平台。我们预计，这种新的方法将提高对癌症治疗的基础理解，为纳米级抗癌药物的设计提供指导原则，并最终导致基于分子自组装和酶催化相结合的癌症治疗的新范式。