NIBIB Supplement to Promote Diversity in Health-Related Research: Targeting of Bioorthogonal Chemotherapeutic Nanozymes to Tumor-Associated Macrophages

NIBIB 补充剂促进健康相关研究的多样性：生物正交化疗纳米酶靶向肿瘤相关巨噬细胞

• 批准号: 10685774
• 负责人: VINCENT M. ROTELLO
• 金额: $ 2.62万
• 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/10685774
• 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; National Institute of Biomedical Imaging and Bioengineering; 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.

项目总结/摘要 生物正交纳米酶对肿瘤相关大分子的靶向作用 在我们提出的研究中，我们将使用生物正交化学靶向肿瘤相关巨噬细胞 （TAMs）在乳腺癌中，使用生物正交化学将它们变成“药物工厂”平台， 在肿瘤部位进行化疗我们将使用我们的'纳米酶'平台来封装和保护过渡 金纳米颗粒（AuNP）单层内的金属催化剂（TMC）。这些纳米酶会被 甘露糖受体在TAM中强烈上调。预计这些纳米酶的全身递送 为肿瘤中高度可及的TAM提供有效定位。随后给予非- 然后毒性前药将提供定位于肿瘤部位的化疗剂的释放。 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 纳米酶通过“隐形”两性离子涂层和合适的靶向元件用于选择性TAM摄取。的 纳米酶的靶向和治疗功效将使用单培养物和共培养物模型在体外定量， 然后，优化的颗粒将被向下选择用于体内评价。我们的具体目标是： 目的1：生物正交纳米酶的制备。目标：单层结构的工程化，以提供高度 活性和稳定的纳米酶。我们将制造涂有两性离子层的纳米酶， 非特异性摄取和甘露糖靶向TAM。我们将优化催化剂负载和血清中的稳定性， 并测定催化剂与前药的反应性。 目的2：体外活性和靶向研究。假设：靶向纳米酶将提供高度细胞选择性 前药的活化。我们将通过纳米酶的催化活性来量化纳米酶在细胞中的细胞内活性。 释放前染料和前药。将评估TAM靶向疗效与非极化疗效 巨噬细胞和其他细胞，以及使用共培养模型测定的体外治疗功效， 基于特异性、功效/治疗窗口和时间来优化系统。 目的3：靶向体内前药活化。假设：靶向纳米酶将定位前药活化 肿瘤部位，提供高效的肿瘤治疗。我们会全身注射甘露糖- 使用4 T1原位乳腺癌在肿瘤部位激活前荧光团和前药的靶向纳米酶 癌模型。将使用以下方法获得定量肿瘤和肿瘤内纳米酶分布： 电感耦合质谱法，以及通过肿瘤大小和小鼠健康量化的功效。 该项目的总体目标是使用通常保护肿瘤的TAM进行治疗性“柔术” 以提供用于向肿瘤高度局部化的治疗递送的发射点。这种生物正交疗法 相对于目前的治疗策略， 化疗方法。