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

• 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
• 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

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).

项目总结/摘要 超分子生物正交纳米酶用于靶向激活 Therapeutics 在我们提出的研究中，我们将创造“纳米酶”-纳米颗粒， 蛋白质样大小和表面性质，催化生物正交过程， 过渡金属中心这些纳米酶将用于激活肿瘤前药 位点，利用纳米酶的生物正交能力靶向肿瘤，产生 在目标组织的治疗。我们将使用体外模型评估这些颗粒 以确定细胞内治疗/成像功效、靶向效率和溶血性 特性.然后将在体内测试这些颗粒，评估它们在两种情况下的功效。 成像和治疗背景。在我们的研究中，我们将 目的1：制备具有不同单层设计的纳米酶， 颗粒负载和催化剂稳定性。我们将量化这些催化效率 用于活化前药的纳米酶，并测定其稳定性。 目的2：通过激活细胞中的前体蛋白来检测纳米酶的细胞内活性。 荧光团和前药。我们将把Her-2目标元件 纳米酶和EGFR靶向肽到聚合物前药递送颗粒， 并确定使用纳米酶和载体的双重“AND”靶向的能力， 只针对过表达两种受体的细胞。 目的3：利用靶向纳米酶激活肿瘤的前体药物和荧光团 原位乳腺癌模型。 目的4：靶向纳米酶和PEG/PLGA纳米粒载药 将用于仅在过表达靶向和非靶向的肿瘤中提供治疗功效。 受体，提供高度特异性的与门靶向。 这项研究的目标是创造能够高度特异性的治疗系统 通过生物正交化学。这项研究将建立在超分子和 Rotello的纳米材料强度结合癌症生物学和动物模型 D.的优势约瑟夫杰里（马萨诸塞州兽医和阿尼。Sci）。