Supramolecular Bioorthogonal Nanozymes for Targeted Activation of Therapeutics

项目摘要/摘要 用于靶向激活的超分子生物正交纳米酶 治疗学 在我们提议的研究中，我们将创造“纳米酶”--纳米粒子，其特征是 类蛋白质的大小和表面性质，催化生物正交过程 过渡金属中心。这些纳米酶将被用来激活肿瘤中的前药物 利用纳米酶的生物正交能力来靶向肿瘤，产生 针对目标组织的治疗。我们将使用体外模型评估这些颗粒 确定细胞内治疗/成像效果、靶向效率和溶血 属性。然后，这些颗粒将在体内进行测试，评估它们在两种情况下的疗效 成像和治疗环境。在我们建议的研究中，我们会 目标1：制备具有不同单层设计的纳米酶以进行优化 颗粒负载量和催化剂稳定性。我们将量化这些化合物的催化效率 用于激活前体药物的纳米酶，并测定其稳定性。 目的2：通过激活酶原来检测细胞内纳米酶的活性 荧光团和前药。我们会将HER-2目标元素附加到 纳米酶和EGFR靶向多肽到聚合物前药物递送颗粒， 并确定使用纳米酶和载体的双重靶向的能力 只针对过度表达两种受体的细胞。 目的3：使用靶向纳米酶激活肿瘤中的前荧光团和前药物 使用原位乳腺癌模型的站点。 目的4：不同靶向的纳米酶和载药前药的聚乙二醇聚乳酸纳米粒 将仅用于治疗过度表达两种靶向的肿瘤 受体，提供高度特异性和门靶向。 这项研究的目标是创造出具有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 ROTELO纳米材料强度与肿瘤生物学和动物模型的耦合 D·约瑟夫·曾傑瑞(美国马萨诸塞州兽医)的优势还有阿尼。SCI)。

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).