RIG-I Activating Nanoparticles for Immunopotentiation

用于免疫增强的 RIG-I 激活纳米颗粒

• 批准号: 10566342
• 负责人: Anna Marie Pyle
• 金额: $ 60.57万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-30 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10566342
• 关键词: Address; Affinity; Agonist; Antiviral Agents; Artificial nanoparticles; Beds; Behavior; Biodistribution; Biological; Cations; Charge; Chemicals; Clinical; Cytosol; Data; Development; Disease; Double-Stranded RNA; Drug Delivery Systems; Drug Kinetics; Endosomes; Engineering; Foundations; Generations; Genes; Half-Life; Hydrophobicity; Immune Targeting; Immune checkpoint inhibitor; Immunobiology; Immunologics; Immunosuppression; Immunotherapeutic agent; Inflammatory; Inflammatory Response; Innate Immune Response; Innate Immune System; Interdisciplinary Study; Interferon Type I; Investigation; Knowledge; Lead; Length; Libraries; Modality; Modeling; Molecular; Mus; Natural Immunity; Oligonucleotides; Organism; Outcome; Pathway interactions; Pattern recognition receptor; Pharmacologic Substance; Pharmacology; Polymer Chemistry; Polymers; Positioning Attribute; Predisposition; Property; RNA; Research; Safety; Science; Site; Structure; Technology; Testing; Therapeutic; Tissues; Toxic effect; Transfection; Translations; Tretinoin; Tumor Immunity; Vaccine Adjuvant; Virus Diseases; adaptive immunity; antitumor effect; base; cancer immunotherapeutics; cancer immunotherapy; clinical application; combinatorial; cytotoxicity; design; drug development; efficacy evaluation; immune activation; immunogenic; immunogenicity; improved; in vivo; in vivo evaluation; innovation; insight; lead candidate; melanoma; mouse model; multidisciplinary; nanocarrier; nanomedicine; nanoparticle; new technology; next generation; novel; nuclease; pharmacokinetics and pharmacodynamics; pre-clinical; preclinical development; preclinical evaluation; prevent; programs; response; stem; therapeutic RNA; tumor; tumor growth; tumor microenvironment; uptake

PROJECT SUMMARY The innate immune system can be pharmacologically programed to elicit desired immunological outcomes. Retinoic acid-inducible gene I (RIG-I) is a pattern recognition receptor that has emerged as a promising innate immune target for immunopotentiation. RIG-I is activated upon recognizing 5’-triphosphorylated, double- stranded RNA (3pRNA) in the cytosol, which stimulates an antiviral-like inflammatory program that can be harnessed to treat or prevent a diversity of diseases. However, the potency and efficacy of 3pRNA has been limited by major drug delivery barriers, including nuclease degradation, inefficient cellular uptake and cytosolic delivery, and rapid clearance. To address these challenges, we have developed RIG-I activating nanoparticles (RANs). RANs are polymer nanoparticles that are engineered to promote the cytosolic delivery of synthetic, molecularly-defined, and high-affinity stem-loop RNA (SLR) RIG-I agonists recently developed by our team. The objective of this R01 application is to optimize and advance RANs as a versatile platform for pharmacological activation of RIG-I. We will accomplish this through the following Specific Aims. First, we will engineer next-generation RANs with improved properties for systemic administration through optimization of SLR and polymer charge and hydrophobicity. This approach will leverage combinatorial chemical diversity to access a new design space for 3pRNA delivery, which we expect will yield next-generation RANs with higher SLR loading efficiency, reduced cytotoxicity, protection from nuclease degradation, improved stability, and enhanced immunostimulatory activity. Second, we will establish relationships between RAN properties, innate immune activation, pharmacokinetics, polymer and SLR biodistribution, and toxicity. These studies are essential in the preclinical development of new immunotherapeutic modalities and will also yield new insight into how nanocarriers can be engineered for safe and effective activation of RIG-I. We expect these studies to yield next-generation RANs that are optimized for systemic administration of SLR therapeutics. Third, while RANs have broad potential clinical applications, we will evaluate their efficacy as a systemically administered cancer immunotherapy in poorly immunogenic mouse models of melanoma as a clinically important test case. We expect to demonstrate that systemic administration of lead-candidate RANs will activate RIG-I in the tumor microenvironment, resulting in an immunological reprograming of tumor sites that inhibits tumor growth and synergizes with immune checkpoint inhibitors. Collectively, these studies will position RANs as an enabling platform for immunopotentiation with potential to address the significant need for new cancer immunotherapies, antiviral agents, and vaccine adjuvants.

项目概要 先天免疫系统可以通过药理学编程来引发所需的免疫结果。 视黄酸诱导基因 I (RIG-I) 是一种模式识别受体，已成为一种有前途的先天性受体。 免疫增强的免疫靶标在识别 5'-三磷酸化、双-后被激活。 胞浆中的链状 RNA (3pRNA)，可刺激抗病毒样炎症程序 用于治疗或预防多种疾病。 然而，3pRNA 的效力和功效已被证实 受到主要药物递送障碍的限制，包括核酸酶降解、低效的细胞摄取和胞质 为了应对这些挑战，我们开发了 RIG-I 激活纳米粒子。 (RAN) 是聚合物纳米粒子，旨在促进合成、 我们的团队最近开发了分子定义的高亲和力茎环 RNA (SLR) RIG-I 激动剂。 该 R01 应用程序的目标是优化和推进 RAN 作为多功能平台 RIG-I 的药理学激活 我们将通过以下具体目标来实现这一目标。 通过优化设计下一代 RAN，使其具有改进的系统管理特性 SLR 和聚合物电荷和疏水性该方法将利用组合化学多样性。 进入 3pRNA 传递的新设计空间，我们预计这将产生具有更高性能的下一代 RAN SLR 装载效率、降低细胞毒性、防止核酸酶降解、提高稳定性，以及 其次，我们将建立 RAN 特性与先天性之间的关系。 这些研究包括免疫激活、药代动力学、聚合物和 SLR 生物分布以及毒性。 对于新的免疫治疗方式的临床前开发至关重要，也将产生新的见解 我们希望这些研究能够研究如何设计纳米载体以安全有效地激活 RIG-I。 第三，产生针对 SLR 疗法的全身给药进行优化的下一代 RAN。 RAN 具有广泛的潜在临床应用前景，我们将评估其作为系统给药药物的功效 黑色素瘤免疫原性差的小鼠模型中的癌症免疫治疗作为临床重要的测试案例。 我们期望证明先导候选 RAN 的全身给药将激活肿瘤中的 RIG-I 微环境，导致肿瘤位点的免疫重编程，抑制肿瘤生长 总的来说，这些研究将 RAN 定位为一种赋能药物。 免疫增强平台有可能满足新癌症免疫疗法的巨大需求， 抗病毒剂和疫苗佐剂。