Targeting of Bio-orthogonal Chemotherapeutic Nanozymes to Tumor-Associated Macrophages

生物正交化疗纳米酶靶向肿瘤相关巨噬细胞

• 批准号: 10578840
• 负责人: VINCENT M. ROTELLO
• 金额: $ 34.52万
• 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 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10578840
• 关键词: 4T1; Cancer Biology; Cells; Chemistry; Coculture Techniques; Coupled; Cytoprotection; Development; Dyes; Elements; Encapsulated; Engineering; Generations; Goals; Health; Immunology; In Situ; In Vitro; Injections; Ligands; Macrophage; Mannose; Mass Spectrum Analysis; Modeling; Modification; Mus; Pharmaceutical Preparations; Phenotype; Play; Porphyrins; Process; Prodrugs; Research; Role; Serum; Site; Specificity; Structure; System; Therapeutic; Transition Elements; Treatment Efficacy; Tumor-associated macrophages; Validation; cancer cell; cancer therapy; catalyst; chemotherapy; efficacy evaluation; fabrication; fluorophore; in vitro activity; in vivo; in vivo evaluation; malignant breast neoplasm; mannose receptor; monolayer; mouse model; nanoGold; nanomaterials; nanoparticle; nanotherapeutic; nanovector; neoplastic cell; orthotopic breast cancer; particle; pre-clinical; scaffold; targeted delivery; targeted treatment; tumor; uptake

Project Summary/Abstract Targeting of Bioorthogonal Chemotherapeutic Nanozymes to Tumor-Associated Macrophages In our proposed research we will use bioorthogonal chemistry to target tumor-associated macrophages (TAMs) in breast cancer, using bioorthogonal chemistry to turn them into ‘drug factory’ platforms for generation of chemotherapeutics at the tumor site. We will use our ‘nanozyme’ platform to encapsulate and protect transition metal catalysts (TMCs) within the monolayer of gold nanoparticles (AuNPs). These nanozymes will be targeted the mannose receptor strongly upregulated in TAMs. Systemic delivery of these nanozymes is anticipated to provide effective localization to TAMs that are highly accessible in tumors. Subsequent administration of non- toxic prodrugs will then provide uncaging of the chemotherapeutic localized to the tumor site. In our proposed research we will optimize the activity of our nanozyme platform. We will then engineer the nanozymes for selective TAM uptake through ‘stealth’ zwitterionic coating and suitable targeting elements. The targeting and therapeutic efficacy of the nanozymes will be quantified in vitro using mono- and co-culture models, Optimized particles will then be downselected for in vivo evaluation. Our specific aims are: Aim 1: Fabrication of Bioorthogonal Nanozymes. Goal: Engineering of monolayer structure to provide highly active and stable nanozymes. We will fabricate nanozymes coated with a zwitterionic layer to minimize non-specific uptake and mannose to target TAMs. We will optimize catalyst loading and stability in serum, and determine catalyst reactivity with prodrugs. Aim 2: In Vitro Activity and Targeting Studies. Hypothesis: Targeted nanozymes will provide highly cell-selective activation of prodrugs. We will quantify the intracellular activity of nanozymes in cells through catalytic uncaging of prodyes and prodrugs. Targeting efficacy to TAMs will assessed versus unpolarized macrophages and other cells, and in vitro therapeutic efficacy determined using co-culture models, optimizing the system based on specificity, efficacy/therapeutic window, and timing. Aim 3: Targeting of Prodrug Activation In Vivo. Hypothesis: Targeted nanozymes will localize prodrug activation to tumor sites, providing highly effective tumor therapy. We will use systemic injection of mannose- targeted nanozymes to activate profluorophores and prodrugs at tumor sites using 4T1 orthotopic breast carcinoma models. Quantitative tumor and intratumoral nanozyme distributions will be obtained using inductively-coupled mass spectrometry, and efficacy quantified by tumor size and mouse health. The overall goal of this project is to perform therapeutic ‘jiu-jitsu’, using TAMs that normally protect tumors to provide launch points for highly localized therapeutic delivery to tumors. This bioorthogonal therapeutic strategy is expected to reduce off-target effects and increase therapeutic efficacy relative to current chemotherapeutic approaches.

项目摘要/摘要 生物正交化疗纳米酶靶向肿瘤相关巨噬细胞的研究 在我们提出的研究中，我们将使用生物正交化学来靶向肿瘤相关的巨噬细胞。 (TAMS)在乳腺癌中，使用生物正交化学将其转化为生成的药物工厂平台 肿瘤部位的化疗药物。我们将使用我们的‘Nanzyme’平台来封装和保护过渡 金纳米颗粒(AuNPs)单层中的金属催化剂(TMC)。这些纳米酶将成为靶标 甘露糖受体在TAMs中强烈上调。这些纳米酶的系统递送有望 为TAM提供有效的定位，在肿瘤中非常容易获得。随后对非- 有毒的前体药物将使肿瘤局部的化疗药物失效。 在我们提出的研究中，我们将优化我们的纳米酶平台的活性。然后我们将设计出 通过“隐形”两性离子涂层和合适的靶向元件选择性摄取的纳米酶。这个 纳米酶的靶向和治疗效果将在体外使用单一和联合培养模型进行量化， 然后，将向下选择优化后的粒子进行体内评估。我们的具体目标是： 目的1：制备生物正交型纳米酶。目标：设计单层结构以提供高度的 活性稳定的纳米酶。我们将制作覆盖有两性离子层的纳米酶，以使 靶向TAMs的非特异性摄取和甘露糖。我们将优化催化剂的负载和血清中的稳定性， 并测定催化剂与前体药物的反应性。 目的2：体外活性和靶向性研究。假设：靶向纳米酶将提供高度的细胞选择性 前药的激活。我们将通过催化作用来量化细胞内纳米酶的活性。 前染剂和前药的停产。将评估靶向TAMS的疗效与未极化的效果 巨噬细胞和其他细胞，以及使用共培养模型确定的体外治疗效果， 根据特异性、疗效/治疗窗口和时机优化系统。 目的3：体内靶向前药活化。假设：靶向纳米酶将定位前药激活 至肿瘤部位，提供高效的肿瘤治疗。我们将使用全身注射甘露糖- 利用4T1原位乳房靶向纳米酶激活肿瘤部位的前荧光团和前药物 肿瘤模型。定量的肿瘤和肿瘤内纳米酶分布将使用 电感耦合质谱仪，并通过肿瘤大小和小鼠健康来量化疗效。 这个项目的总体目标是使用通常保护肿瘤的TAMs进行治疗性的柔术 为高度局部化的肿瘤治疗提供发射点。这是一种生物正交疗法 与当前相比，该战略有望减少偏离目标的影响并提高治疗效果 化疗方法。