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

项目摘要：在高度专业化的纳米粒子设计方面继续取得巨大进展 用于实现优于标准药理学试剂的上级结果的治疗剂，后者通常与 具有限制治疗功效的显著毒性。虽然癌症免疫疗法已经彻底改变了 尽管这些药物用于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，免疫抑制微环境中的免疫相关不良事件和脱靶效应。 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癌症的治疗。 与免疫疗法相结合的持久反应率。一个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-治疗肿瘤而不需要细胞毒性 毒品这些能力由这些材料的固有物理化学性质决定， 导致信号转导途径破坏、细胞串扰或侵入和/或诱导细胞死亡程序 在肿瘤微环境（TME）中，这为对抗疾病提供了前所未有的机会。我们 已经开发了专门的超小荧光核壳二氧化硅纳米颗粒，康奈尔素数点（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 通过铁依赖性的铁凋亡机制诱导癌细胞死亡和（2）调节免疫细胞 直接通过引发T细胞和使巨噬细胞向促炎表型极化。作为CD 8 + T细胞 已知在免疫治疗期间也调节铁凋亡，预期这种作用与那些 由C'点诱导。该提案的一个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性的反应。在目标I中，我们将研究 PEG包被的C'点的结构性质的变化，普通的或修饰的以特异性结合到 黑皮质素-1受体（MC 1-R;一种由我们的同基因小鼠模型过表达的良好确立的靶标， 人黑色素瘤），通过调节铁凋亡影响同系黑色素瘤模型中治疗功效 和肿瘤微环境，在存在和不存在检查点阻断的情况下。在Aim II中，我们将探索 在体外驱动免疫细胞表型调节和/或诱导铁凋亡的潜在机制。的 该项目的成功完成将为以下方面提供重要的见解：（i）调节 这些颗粒的联合自我治疗活性与它们诱导铁凋亡和引发 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 其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）串联。

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).