Macrophage-specific tumor immunotherapy via glycosylated-nanoparticles

通过糖基化纳米颗粒进行巨噬细胞特异性肿瘤免疫治疗

• 批准号: 10392501
• 负责人: Thomas A Werfel
• 金额: $ 25.16万
• 依托单位: UNIVERSITY OF MISSISSIPPI
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-15 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10392501
• 关键词: Affinity; Anticardiolipin Antibodies; Apoptotic; Autoimmunity; Automobile Driving; Binding; Biodistribution; Blood Circulation; Bone Marrow; Breast Cancer Treatment; Cells; Centers of Research Excellence; Characteristics; Chromatin; Chronic; Cytotoxic Chemotherapy; Drug Delivery Systems; Drug Kinetics; Engineering; FOXP3 gene; Formulation; Gene Expression; Goals; Homing; Human; Hydrophobicity; Immunoglobulin G; Immunoglobulin M; Immunosuppression; Immunotherapy; Inflammation; Interleukin-4; Intravenous; Label; Leukocytes; Libraries; Ligands; Liver; Lung; Malignant Neoplasms; Mammary Neoplasms; Mannans; Mannose; Measures; Mediating; Mentors; Micelles; Mississippi; Modeling; Monitor; Mus; Mutation; Necrosis; Neoplasm Metastasis; Organ; Permeability; Phagocytes; Pharmaceutical Preparations; Plasma; Polymers; Polypropylenes; Polysaccharides; Primary Neoplasm; Process; Receptor Protein-Tyrosine Kinases; Regulatory T-Lymphocyte; Research Personnel; Residual state; Retinal Diseases; Rheumatoid Factor; Risk; Signal Transduction; Single-Stranded DNA; Solid Neoplasm; Sulfides; Surface; Techniques; Technology; Therapeutic; Tissues; Treatment Efficacy; Trehalose; Tumor Immunity; Tumor-associated macrophages; Universities; base; compare effectiveness; copolymer; cytokine; cytotoxic; delivery vehicle; density; inhibitor; lupus-like; macrophage; malignant breast neoplasm; mannose receptor; monocyte; nanoparticle; nanotechnology platform; neoplasm immunotherapy; neoplastic; neoplastic cell; novel; orthotopic breast cancer; overexpression; phosphatidylserine receptor; polymerization; prevent; receptor expression; response; side effect; systemic autoimmunity; therapeutic evaluation; treatment response; tumor; tumor growth; tumor microenvironment; tumor progression; uptake

Project 4: Macrophage-specific tumor immunotherapy via glycosylated-nanoparticles Junior Investigator: Thomas Werfel Mentor: Adam Smith, University of Mississippi Efferocytosis, the phagocytic clearance of apoptotic cells, in the tumor microenvironment promotes immunosuppression, dampening anti-tumor immunity and thus the therapeutic response to cytotoxic and immunotherapies. Macrophages are primarily responsible for efferocytosis in the tumor microenvironment, where they recognize apoptotic cells using the phosphatidylserine receptor MerTK and then produce a host of immunosuppressive signals in response to apoptotic cell engulfment. Attempts to block efferocytosis in the tumor microenvironment by inhibiting the activity of MerTK show promise. However, chronic, systemic blockade of MerTK and/or hypomorphic MerTK mutations contribute to inflammation-related retinopathies, lupus-like auto- immunity, and risk of auto-immunity. To circumvent the deleterious effects of auto-immunity associated with chronic systemic inhibition, we propose to target MerTK specifically within tumor-associated macrophages (TAMs) using high-mannose decorated-nanoparticles (hmn-NPs) harboring a MerTK inhibitor. We propose novel synthetic strategies to produce nanoparticles with 1) a polypropylene sulfide core for hydrophobic drug loading and targeted release and 2) a glycopolymer-based corona consisting of a mixture of trehalose and mannose polymers. Trehalose has been shown to impart enhanced stability to drug delivery vehicles and will be crucial for endowing the stability necessary for systemic delivery applications. Mannose has been used to target nanoparticles to TAMs because of their characteristic overexpression of the mannose receptor. However, past strategies have been limited to local delivery applications and have employed monomeric versions of mannose. Our polymeric version of mannose will more closely mimic the natural binding partners for mannose receptor, mannan and high-mannose glycans, which have much higher affinity than monomeric mannose. Thus, a major goal of this project is to rigorously compare the effectiveness of monomeric mannose and polymannose as targeting strategies for TAMs. Using the TAM-targeting hmn-NPs as an enabling technology, we will test the therapeutic impact of TAM-specific MerTK inhibition on immunosuppression in the tumor microenvironment, tumor progression, and systemic auto-immunity.

项目4：通过糖基化纳米颗粒进行巨噬细胞特异性肿瘤免疫治疗 初级研究员：托马斯·韦费尔 导师：亚当·斯密，密西西比大学 在肿瘤微环境中，细胞吞噬作用，即凋亡细胞的吞噬清除， 免疫抑制，抑制抗肿瘤免疫，从而抑制对细胞毒性和 免疫疗法巨噬细胞主要负责肿瘤微环境中的巨噬细胞增多， 它们利用磷脂酰丝氨酸受体MerTK识别凋亡细胞，然后产生大量的 免疫抑制信号响应凋亡细胞吞噬。试图阻断肿瘤中的红细胞增多症 通过抑制MerTK的活性来改善微环境显示出希望。然而，慢性全身性阻断 MerTK和/或亚纯型MerTK突变导致炎症相关视网膜病变、狼疮样自身免疫性视网膜病变和视网膜病变。 免疫力和自身免疫的风险。为了避免与自身免疫相关的有害影响， 慢性全身抑制，我们建议在肿瘤相关巨噬细胞内特异性靶向MerTK 使用含有MerTK抑制剂的高甘露糖修饰的纳米颗粒（hmn-NP）的TAM。我们建议小说 制备纳米颗粒的合成策略，所述纳米颗粒具有1）用于疏水药物负载的聚硫化丙烯核 和靶向释放，以及2）由海藻糖和甘露糖的混合物组成的基于葡糖共聚物的冠 聚合物海藻糖已被证明可以增强药物递送载体的稳定性， 用于赋予系统递送应用所需的稳定性。甘露糖已被用于靶向 纳米颗粒与TAM的结合是因为它们的甘露糖受体的特征性过表达。但过去的 策略局限于局部递送应用，并使用甘露糖的单体形式。 我们的甘露糖的聚合物形式将更接近地模拟甘露糖受体的天然结合伴侣， 甘露聚糖和高甘露糖聚糖，其具有比单体甘露糖高得多的亲和力。由此可见，少校 该项目的目标是严格比较单体甘露糖和聚甘露糖作为 针对TAM的战略。使用靶向TAM的hmn-NP作为使能技术，我们将测试 TAM特异性MerTK抑制对肿瘤微环境中免疫抑制的治疗影响， 肿瘤进展和系统性自身免疫。