Macrophage-specific tumor immunotherapy via glycosylated-nanoparticles

项目4：通过糖基化纳米粒进行巨噬细胞特异性肿瘤免疫治疗 初级调查员：托马斯·维尔费尔 导师：密西西比大学亚当·史密斯 在肿瘤微环境中，有效细胞吞噬作用促进了对凋亡细胞的吞噬清除 免疫抑制，抑制抗肿瘤免疫，从而治疗细胞毒性和 免疫疗法。巨噬细胞主要负责肿瘤微环境中的胞吐作用，其中 他们使用磷脂酰丝氨酸受体MerTK识别凋亡细胞，然后产生一系列 免疫抑制信号对凋亡细胞吞噬的反应。试图阻断肿瘤中的胞吐作用 微环境通过抑制MerTK的活性显示出良好的前景。然而，长期、系统性的封锁 MerTK和/或亚型MerTK突变导致炎症相关的视网膜病变，狼疮样自身 免疫力和自身免疫力的风险。为了避免自身免疫的有害影响， 慢性全身抑制，我们建议在肿瘤相关巨噬细胞中特异性靶向MerTK (TAMS)使用含有MerTK抑制剂的高甘露糖修饰纳米粒(hMN-NPs)。我们提出了小说 制备含1)疏水载药的聚硫化丙烷核纳米粒的合成策略 和靶向释放，以及2)由海藻糖和甘露糖混合物组成的基于糖共聚物的电晕 聚合物。海藻糖已被证明可以增强药物输送载体的稳定性，并将是至关重要的 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 纳米颗粒由于其特有的甘露糖受体过度表达而被转移到TAMs。然而，过去 策略一直局限于本地递送应用，并使用了甘露糖的单体版本。 我们的甘露糖聚合版本将更接近于甘露糖受体的天然结合伙伴， 甘露聚糖和高甘露糖，它们比单体甘露糖具有更高的亲和力。因此，一名少校 本项目的目标是严格比较单体甘露糖和多甘露糖作为 针对TAMS的目标策略。使用目标的HMN-NPs作为使能技术，我们将测试 特异性MerTK抑制剂对肿瘤微环境免疫抑制的治疗作用 肿瘤进展和全身自身免疫。

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.