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: 10405110
• 负责人: VINCENT M. ROTELLO
• 金额: $ 34.6万
• 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/10405110
• 关键词: 4T1; Cancer Biology; Cells; Chemistry; Coculture Techniques; Coupled; Development; Dyes; Elements; Encapsulated; Engineering; Generations; Goals; Health; Immunology; In Situ; In Vitro; Injections; Ligands; 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; base; cancer cell; cancer therapy; catalyst; chemotherapy; fluorophore; in vitro activity; in vivo; in vivo evaluation; macrophage; 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.

项目概要/摘要 生物正交化疗纳米酶靶向肿瘤相关巨噬细胞 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巨噬细胞 （TAM）在乳腺癌中的应用，利用生物正交化学将其转变为“药物工厂”平台以进行生成 我们将使用我们的“纳米酶”平台来封装和保护肿瘤部位的化疗。 单层金纳米颗粒 (AuNP) 内的金属催化剂 (TMC) 将成为这些纳米酶的目标。 预计这些纳米酶的全身递送会显着上调 TAM 中的甘露糖受体。 为肿瘤中易于随后施用的 TAM 提供有效的定位。 然后，有毒前药将释放肿瘤部位的化疗药物。 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，然后我们将设计它。 通过“隐形”两性离子涂层和合适的靶向元件选择性摄取 TAM 的纳米酶。 纳米酶的靶向和治疗功效将使用单一和共培养模型在体外进行量化， 然后将优化的颗粒进行体内评估，我们的具体目标是： 目标 1：生物正交纳米酶的制造 目标：单层结构工程以提供高度的性能。 我们将制造涂有两性离子层的纳米酶，以最大限度地减少活性和稳定的纳米酶。 针对 TAM 的非特异性摄取和甘露糖我们将优化血清中的催化剂负载和稳定性， 并确定催化剂与前药的反应性。 目标 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。 我们将通过催化来量化细胞中纳米酶的细胞内活性。 与非极化相比，将评估前体染料和前药的靶向功效。 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、功效/治疗窗口和时间优化系统。 目标 3：体内前药激活的靶向 假设：靶向纳米酶将定位前药激活。 到肿瘤部位，高度提供有效的肿瘤治疗，我们将使用甘露糖的全身注射。 使用 4T1 原位乳腺靶向纳米酶激活肿瘤部位的前荧光团和前药 定量肿瘤和肿瘤内纳米酶分布将使用以下方法获得 电感耦合质谱法，并通过肿瘤大小和小鼠健康状况量化疗效。 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” 为肿瘤的高度局部治疗提供启动点。 相对于目前的策略，预计将减少脱靶效应并提高治疗效果 化疗方法。