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

项目摘要：随着高度专业化，纳米颗粒的设计继续取得巨大进步 与标准药物制剂相比，获得更好结果的治疗方法，后者通常与 具有显着的毒性，限制了治疗效果。虽然癌症免疫疗法彻底改变了 治疗疾病并在难以治疗的癌症中显示出治疗益处，但这些药物是有限的， 例如，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，迫切需要新的、新兴的抗癌策略来克服这些限制并改善 与免疫疗法相结合的持久缓解率。一项有前途的策略利用了独特的“自我 纳米材料本身的“治疗”能力——无需细胞毒性即可治疗肿瘤 药物。这些能力由这些材料的固有物理化学性质决定，这些性质可以 导致信号转导途径破坏、细胞串扰或入侵、和/或诱导细胞死亡程序 肿瘤微环境（TME）中——为对抗疾病提供了前所未有的机会。我们 开发了专门的超小型荧光核壳二氧化硅纳米颗粒、康奈尔素点（C'点）、 具有内在的治疗能力，可实现不同的活动组合：(1) 选择性地、直接地 通过铁依赖性铁死亡机制诱导癌细胞死亡，并 (2) 调节免疫细胞 直接通过启动 T 细胞并使巨噬细胞极化至促炎表型。作为 CD8 T 细胞 已知在免疫治疗过程中也能调节铁死亡，这种作用预计会与那些作用产生协同作用 由C'点诱导。该提案的长期目标是确定关键的 C' 点物理化学参数 负责最大化对这些内在治疗活动的反应。在目标 I 中，我们将检查范围 PEG 涂层的 C' 点的结构特性发生变化，无论是普通的还是经过修饰的，以特异性结合 黑皮质素-1 受体（MC1-R；我们的同基因小鼠模型过度表达的一个成熟靶标， 人类黑色素瘤），通过调节铁死亡影响同基因黑色素瘤模型的治疗效果 以及存在和不存在检查点封锁时的肿瘤微环境。在目标二中，我们将探究 驱动免疫细胞表型调节和/或体外铁死亡诱导的潜在机制。的 该项目的成功完成将为以下方面提供重要见解：（i）调节 这些颗粒的联合自我治疗活性与其诱导铁死亡和启动 肿瘤免疫微环境； (ii) 所需的颗粒特性是否存在关键差异 优化这些不同的活动； (iii) 支持这些活动的机制； (iv) 治疗策略 通过给予治疗剂量的 颗粒与检查点抑制剂（抗 PD-1 和抗 CTLA-4）联用。

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).