Ultrasmall particle-based solutions for inducing ferroptosis and improving anti-tumor immune responses in cancer

基于超小颗粒的解决方案，用于诱导铁死亡并改善癌症中的抗肿瘤免疫反应

基本信息

批准号：
10888788
负责人：
Michelle S Bradbury
金额：
$ 55.08万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-06-01 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10888788
关键词：
Affinity Antitumor Response Automobile Driving Binding Biology CD8-Positive T-Lymphocytes Cancerous Cell Death Cell Death Induction Cells Characteristics Chemicals Cytotoxic agent Data Dimensions Disease Dose Encapsulated Exhibits Fluorescent Dyes Gel Chromatography Genetic Engineering Goals High Pressure Liquid Chromatography Human Immune Immune checkpoint inhibitor Immune response Immunotherapy In Vitro Inflammatory Inflammatory Response Intravenous Invaded Iron Lead Lesion Link Lipid Peroxides Macrophage Malignant Neoplasms Melanocortin 1 Receptor Melanoma Cell Modeling Molecular Mus Mutation Necrosis Outcome Pathway interactions Pharmaceutical Preparations Phenotype Population Process Property Research Research Design Series Signal Transduction Pathway Silicon Dioxide T-Lymphocyte Therapeutic Therapeutic Effect Time Toxic effect Translations Transplantation Treatment Efficacy anti-CTLA4 anti-PD-1 anti-cancer anti-cancer therapeutic anti-tumor immune response anticancer activity antitumor effect aqueous cancer cell cancer immunotherapy cancer regression cancer therapy carcinogenesis combat cytokine design experimental study immune checkpoint blockade immune-related adverse events immunoregulation improved in vivo inhibitor insight intravenous administration melanoma mouse model nanomaterials nanoparticle nanotherapeutic novel overexpression particle pharmacologic programs recruit response small molecule synergism treatment response tumor tumor microenvironment tumor-immune system interactions

项目摘要

Project Summary: Enormous strides continue to be made in the design of nanoparticles as highly specialized therapeutics for achieving superior outcomes over standard pharmacological agents, the latter often associated with significant toxicity that limits treatment efficacy. While cancer immunotherapies have revolutionized the treatment of disease and shown therapeutic benefits in hard-to-treat cancers, these agents are limited, for example, by immune-related adverse events and off-target effects in immunosuppressive microenvironments. Novel, emerging anti-cancer strategies are therefore critically needed to overcome these limitations and improve durable response rates in combination with immune therapies. One promising strategy exploits the unique “self- therapeutic” capabilities of the nanomaterials themselves – the treatment of tumors without the need for cytotoxic drugs. These capabilities are governed by the intrinsic physico-chemical properties of these materials, which can lead to disruption of signal transduction pathways, cell cross-talk or invasion, and/or induced cell death programs within the tumor microenvironment (TME) – providing unprecedented opportunities for combating disease. We have developed specialized ultrasmall fluorescent core-shell silica nanoparticles, Cornell prime dots (C' dots), with intrinsic therapeutic capabilities enabling a distinct combination of activities that (1) selectively and directly induce cancer cell death through the iron-dependent mechanism of ferroptosis and (2) modulate immune cells directly by priming T cells and polarizing macrophages toward a pro-inflammatory phenotype. As CD8+ T cells are known to also regulate ferroptosis during immunotherapy, such effects are expected to synergize with those induced by C' dots. A long-term goal of this proposal is to determine critical C' dot physico-chemical parameters responsible for maximizing responses to these intrinsic therapeutic activities. In Aim I, we will examine the extent to which changes in the structural properties of PEG-coated C' dots, plain or modified to specifically bind to melanocortin-1 receptor (MC1-R; a well-established target overexpressed by our syngeneic murine models and human melanomas), influence therapeutic efficacy in syngeneic melanoma models by modulating ferroptosis and the tumor microenvironment, in the presence and absence of checkpoint blockade. In Aim II, we will probe underlying mechanisms driving regulation of immune cell phenotype and/or induction of ferroptosis in vitro. The successful completion of the project will provide critical insights into (i) key structural parameters modulating the combined self-therapeutic activities of these particles related to their induction of ferroptosis and priming the tumor immune microenvironment; (ii) whether critical differences exist in particle characteristics needed to optimize these distinct activities; (iii) mechanisms underpinning these activities; and (iv) therapeutic strategies that maximize potent anti-tumor effects in syngeneic melanoma models by administering therapeutic doses of particles in tandem with checkpoint inhibitors (anti-PD-1 and anti-CTLA-4).

项目摘要：作为高度专业化实现优于标准药剂的卓越结果的治疗剂，后者通常与具有限制治疗效率的明显毒性。而癌症免疫疗法彻底改变了疾病的治疗并显示出难以治疗的癌症的治疗益处，这些药物是有限的，因为例如，通过免疫相关的不良事件和免疫抑制微环境中的脱靶效应。因此，需要新颖的，新兴的反癌战略来克服这些局限性并改善耐用的应答率与免疫疗法结合使用。一种承诺策略利用了独特的“自我纳米材料本身的治疗能力 - 肿瘤的治疗无需细胞毒性毒品。这些功能受这些材料的内在物理化学特性的控制，可以导致信号转导途径，细胞串扰或入侵和/或诱导的细胞死亡程序的破坏在肿瘤微环境（TME）中 - 为抗击疾病提供了前所未有的机会。我们已经开发了专门的超湿荧光芯壳二氧化硅纳米颗粒，康奈尔素点（C'DOTS），具有固有的治疗能力，实现了（1）直接和直接的活动的独特组合通过铁铁作用的铁依赖机制诱导癌细胞死亡，（2）调节免疫细胞直接通过启动T细胞并将巨噬细胞偏振朝向促炎的表型。作为CD8+ T细胞已知还可以调节免疫疗法期间的铁铁作用，这种影响有望与由c'点诱导。该建议的长期目标是确定关键的C'DOT物理化学参数负责最大化对这些内在治疗活动的反应。在目标一世中，我们将检查范围 peg涂层的C'点的结构特性变化，纯正或修改以特异性结合黑素皮质素-1受体（MC1-R；由我们的合成鼠模型过表达的良好靶标和人类黑色素瘤），通过调节铁铁蛋白作用，影响疗法的有效性在存在和不存在检查点阻塞的情况下，肿瘤微环境。在AIM II中，我们将证明驱动免疫球表型调节的基本机制和/或体外诱导铁凋亡的诱导。这项目的成功完成将为（i）调制关键结构参数提供关键见解这些颗粒与它们诱导的螺旋病和启动有关的自我治疗活性的结合肿瘤免疫微环境；（ii）在需要的粒子特征中是否存在关键差异优化这些不同的活动；（iii）基于这些活动的机制；（iv）治疗策略通过给予治疗剂量与检查点抑制剂（抗PD-1和抗CTLA-4）相连的颗粒。