Supramolecular Bioorthogonal Nanozymes for Targeted Activation of Therapeutics

用于靶向激活治疗药物的超分子生物正交纳米酶

基本信息

批准号：
9305701
负责人：
VINCENT M. ROTELLO
金额：
$ 34.69万
依托单位：
UNIVERSITY OF MASSACHUSETTS AMHERST
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-05-01 至 2021-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9305701
关键词：
Animal Model Behavior Biomimetics Breast Carcinoma Caliber Cancer Biology Catalysis Cells Chemicals Chemistry Coupled Development Elements Encapsulated Engineering Environment Epidermal Growth Factor Receptor Family Goals Gold Health Hydrophobicity Image In Situ Logic Mediating Modeling Palladium Peptides Pharmaceutical Preparations Polymers Polystyrenes Process Prodrugs Property Proteins Reaction Research Serum Site Specificity Structure Surface Properties System Testing Therapeutic Therapeutic Agents Tissues Toxic effect Transition Elements Treatment Efficacy Validation base biomaterial compatibility bioprocess cancer cell catalyst chemotherapy design fluorophore image reconstruction imaging agent in vitro Model in vitro activity in vivo monolayer mouse model nanomaterials nanoparticle overexpression particle pre-clinical receptor scaffold tumor tumor specificity water solubility

项目摘要

Project Summary/Abstract Supramolecular Bioorthogonal Nanozymes for Targeted Activation of Therapeutics In our proposed research we will create "nanozymes"—nanoparticles featuring protein-like size and surface properties that catalyze bioorthogonal processes using transition metal centers. These nanozymes will be used to activate prodrugs at tumor sites, using the bioorthogonal capabilities of the nanozyme to target tumors, generating therapeutics at the targeted tissue. We will assess these particles using in vitro models to determine intracellular therapeutic/imaging efficacy, targeting efficiency, and hemolytic properties. The particles will then be tested in vivo, assessing their efficacy in both imaging and therapeutic contexts. In our proposed studies, we will Aim 1: Fabricate nanozymes featuring different monolayer designs for optimizing particle loading and catalyst stability. We will quantify catalytic efficiency of these nanozymes for activating prodrugs, and determine their stability. Aim 2: Test the intracellular activity of nanozymes in cells through activation of pro- fluorophores and prodrugs. We will attach Her-2 targeting elements to the nanozymes and EGFR-targeting peptides to the polymeric prodrug delivery particles, and determine the ability to use dual "AND" targeting of nanozyme and carrier to target only cells that overexpress both receptors. Aim 3: Use targeted nanozymes to activate profluorophores and prodrugs at tumor sites using orthotopic breast carcinoma models. Aim 4: Differently targeted nanozymes and PEG/PLGA nanoparticles carrying prodrug will be used to provide therapeutic efficacy only at tumors overexpressing both targeted receptors, providing highly specific AND gate targeting. The goal of this research is to create therapeutic systems capable of high specificity through bioorthogonal chemistry. This research will build upon the supramolecular and nanomaterials strength of Rotello coupled with the cancer biology and animal model strengths of D. Joseph Jerry (UMass Vet. and Ani. Sci).

项目概要/摘要用于靶向激活的超分子生物正交纳米酶疗法在我们提出的研究中，我们将创造“纳米酶”——具有类似蛋白质的大小和表面特性，利用催化生物正交过程这些纳米酶将用于激活肿瘤的前药。位点，利用纳米酶的生物正交能力来靶向肿瘤，产生我们将使用体外模型评估这些颗粒的治疗效果。确定细胞内治疗/成像功效、靶向效率和溶血然后将在体内测试这些颗粒的特性，评估它们在这两个方面的功效。在我们提出的研究中，我们将进行成像和治疗方面的研究。目标 1：制造具有不同单层设计的纳米酶以进行优化我们将量化这些的催化效率。用于激活前药的纳米酶，并确定其稳定性。目标 2：通过激活亲细胞来测试细胞中纳米酶的细胞内活性我们将把 Her-2 靶向元件附加到荧光团和前药上。纳米酶和 EGFR 靶向肽至聚合前药递送颗粒，并确定使用纳米酶和载体的双重“AND”靶向的能力仅针对过度表达两种受体的细胞。目标 3：使用靶向纳米酶激活肿瘤中的前荧光团和前药使用原位乳腺癌模型的站点。目标 4：不同靶向的纳米酶和携带前药的 PEG/PLGA 纳米颗粒将仅用于在过度表达两种靶标的肿瘤中提供治疗功效受体，提供高度特异性的 AND 门靶向。这项研究的目标是创建具有高特异性的治疗系统这项研究将建立在超分子和生物正交化学的基础上。 Rotello 的纳米材料优势与癌症生物学和动物模型相结合 D. Joseph Jerry（麻省大学兽医和动物科学）的优势。