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

项目摘要：高度专业化的纳米粒子的设计继续取得巨大进展 治疗取得优于标准药理药剂的疗效，后者通常与 具有显著的毒性，限制了治疗效果。虽然癌症免疫疗法已经彻底改变了 对于难以治疗的癌症，这些药物对疾病的治疗和显示的治疗效果是有限的， 例如，通过免疫相关的不良事件和免疫抑制微环境中的非靶点效应。 因此，迫切需要新的、新兴的抗癌策略来克服这些限制并改进 与免疫疗法相结合的持久应答率。一种很有前途的策略是利用独特的“自我-- 纳米材料本身的治疗能力--不需要细胞毒性就能治疗肿瘤 毒品。这些能力受这些材料的内在物理化学性质的支配，这些性质可以 导致信号转导通路中断，细胞串扰或侵袭，和/或诱导细胞死亡程序 在肿瘤微环境(TME)内--为抗击疾病提供了前所未有的机会。我们 已经开发出专门的超小荧光核壳二氧化硅纳米颗粒，康奈尔质点(C‘点)， 具有内在的治疗能力，能够实现以下活动的独特组合：(1)选择性地和直接地 通过铁依赖的下垂机制诱导癌细胞死亡；(2)调节免疫细胞 直接通过激发T细胞和使巨噬细胞偏向致炎表型。作为CD8 T细胞 在免疫治疗过程中也可以调节铁性下垂，这种作用有望与 由C‘点诱导。这项提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Aim I中，我们将检查 聚乙二醇包覆的C‘点的结构性质的变化，无论是普通的还是特殊结合的 黑素皮质素-1受体(MC1-R；一个公认的靶点，在我们的同基因小鼠模型和 人类黑色素瘤)，通过调节铁下垂影响同基因黑色素瘤模型的治疗效果 以及肿瘤的微环境，在有无关卡封锁的情况下。在AIM II中，我们将探索 在体外调节免疫细胞表型和/或诱导铁性下垂的潜在机制。这个 该项目的成功完成将为以下方面提供关键的见解：(I)调整 这些颗粒的联合自我治疗活性与其诱导铁性下垂和启动 肿瘤免疫微环境；(Ii)是否存在关键的颗粒特性差异 优化这些不同的活动；(3)支持这些活动的机制；和(4)治疗策略 在同基因黑色素瘤模型中通过给予治疗性剂量的 与检查点抑制剂(抗PD-1和抗CTLA-4)联合使用的颗粒。

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).