Systemic delivery of siRNA by Nanosac for checkpoint blockade immunotherapy of head and neck squamous cell cancer

Nanosac 系统性递送 siRNA 用于头颈鳞状细胞癌的检查点阻断免疫治疗

• 批准号: 10182630
• 负责人: Stephen J. Kron
• 金额: $ 60.2万
• 依托单位: PURDUE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10182630
• 关键词: Adopted; Albumins; Antibodies; Binding; Biodistribution; Biological; Blocking Antibodies; Blood Circulation; CD47 gene; Cations; Cessation of life; Characteristics; Charge; Chemotherapy and/or radiation; Clinic; Development; Diagnosis; Disease; Drug Delivery Systems; Drug Kinetics; Environment; Formulation; Future; Gene Delivery; Gene Targeting; Genes; Goals; Head and Neck Cancer; Head and Neck Squamous Cell Carcinoma; Ice; Image; Imaging Device; Immune; Immunosuppression; Immunotherapy; In Vitro; Malignant Neoplasms; Mediating; Methods; Mission; Modeling; Nature; Nucleic Acids; Oral cavity; Permeability; Pharmacodynamics; Pharyngeal structure; Porosity; Production; Public Health; RNA Interference; Radiation; Recovery; Recurrence; Regulatory Pathway; Research; Research Personnel; Resistance; Resources; Safety; Signal Transduction; Silicon Dioxide; Small Interfering RNA; Solid Neoplasm; Surface; Synthetic Genes; System; Systemic Therapy; Testing; Therapeutic; Therapeutic Effect; Thick; Three-Dimensional Imaging; Time; Tissues; Toxic effect; Translations; Tumor Immunity; United States National Institutes of Health; Work; base; cancer therapy; capsule; chemotherapy; clinical translation; design; human disease; image guided; image-guided radiation; immune checkpoint blockade; improved; innovation; intravenous injection; irradiation; nanocapsule; nanomedicine; nanoparticle; neoplastic cell; novel; prevent; programmed cell death ligand 1; response; siRNA delivery; standard of care; success; targeted agent; targeted cancer therapy; targeted imaging; therapeutic siRNA; tomography; tumor; tumor growth; tumor microenvironment; tumor-immune system interactions; uptake

ABSTRACT Head and neck cancer is currently treated by concomitant chemotherapy and radiation, but local recurrence and metastatic disease remain a concern. In particular, there is a pressing need to improve treatment for advanced and metastatic head and neck squamous cell cancer (HNSCC), which has a median survival of 6 to 12 months, even with aggressive chemotherapy, alone or combined with radiation or targeted agents. Checkpoint blockade immunotherapies (CBI) with antibodies have been tried only to achieve a 20-30% response rate. Resistance to immunotherapy in HNSCC is partly attributable to the comprehensive nature of immunosuppression, where the blockade of one checkpoint can be counterbalanced by another negative regulatory pathway, and the transient nature of target-antibody engagement, allowing rapid recovery of suppressive signals. Given these challenges, siRNAs are considered a promising alternative to antibodies to enhance the benefits of CBI, based on modularity of siRNA, enabling multi-targeted therapy, and the potential for RNA interference to provide long-lasting effects. However, without a means for reliable tumor delivery, siRNA will remain sidelined for CBI and other targeted cancer therapies. Developing a safe nucleic acid carrier that achieves favorable biodistribution and tumor cell uptake upon intravenous injection would overcome the critical barrier to clinical translation of siRNA therapeutics in cancer. The Objective of this study is to enable systemic gene delivery to tumors using Nanosac, a novel soft, non-cationic polydopamine nanocapsule, which holds siRNA inside and adopts a corona of native albumin in circulation. We produce Nanosac by coating mesoporous silica nanoparticles (MSN) with siRNA, then with pol- ydopamine, and removing the sacrificial MSN core. Nanocore delivers siRNA and silences target genes with no toxicity in vitro, binds albumin, and readily extravasates and penetrates into tumors, and suppresses tumor growth as a systemic carrier of siRNA targeting PD-L1. Our Central Hypothesis is that while the cationic charge and/or exposure of nucleic acid typical of conventional synthetic gene carriers compromise circulation time, de- livery to tumors, and safety, Nanosac will overcome these challenges by its softness, encapsulation of siRNA and the non-cationic, albuminylated surface. To test this hypothesis, we will pursue three Specific Aims: (i) To optimize design and production of Nanosac for multigene targeting; (ii) To define toxicity, pharmacokinetics (PK), biodistribution (BD), and pharmacodynamics of Nanosac; (iii) To leverage systemic delivery of Nanosac and tumor targeting by image-guided radiation. The Core Innovation of this strategy is that we have pioneered Nanosac, a non-toxic, non-cationic, soft nanocapsule as a nucleic acid carrier, which overcomes limitations of conventional gene carriers, which rely on cationic charges for loading and intracellular delivery. Thereby, we have the potential not only to overcome the persistent challenge in systemic delivery of siRNA to solid tumors but to open the door to a wide range of other gene-targeting strategies.

摘要 头颈癌目前采用同期化疗和放射治疗，但局部复发和 转移性疾病仍然是一个令人担忧的问题。特别是，迫切需要改善晚期癌症的治疗。 以及转移性头颈部鳞状细胞癌(HNSCC)，中位生存期为6至12个月， 即使是积极的化疗，单独或与放射或靶向药物联合使用。检查站封锁 使用抗体的免疫疗法(CBI)仅被尝试达到20%-30%的应答率。抵抗力 HNSCC的免疫治疗部分归因于免疫抑制的综合性，其中 一个检查站的封锁可以被另一个负面的调控途径抵消，而瞬时的 靶-抗体结合的性质，允许抑制信号的快速恢复。鉴于这些挑战， 基于模块化，siRNAs被认为是一种很有前途的抗体替代品，可以增强CBI的好处 SiRNA的作用，使多靶点治疗成为可能，以及RNA干扰提供长期效应的可能性。 然而，如果没有可靠的肿瘤传递手段，siRNA将继续对CBI和其他靶向治疗持观望态度 癌症疗法。开发一种实现良好生物分布和肿瘤细胞的安全核酸载体 静脉注射摄取将克服siRNA疗法临床翻译的关键障碍 在癌症中。 这项研究的目的是使用Nanosac，一种新型的软， 非阳离子多巴胺纳米胶囊，内部含有siRNA，并采用天然白蛋白的电晕 发行量。我们通过在介孔二氧化硅纳米颗粒(MSN)上包覆siRNA，然后用Poll-RNA包覆来制备Nanosac。 以及移除牺牲的MSN核心。纳米核传递siRNA并使靶基因沉默而不带NO 体外毒性，结合白蛋白，容易渗入和渗透到肿瘤中，抑制肿瘤 作为针对PD-L1的siRNA的系统载体生长。我们的中心假设是，虽然阳离子电荷 和/或传统合成基因载体典型的核酸暴露会危及循环时间，去... 对肿瘤的粘附性和安全性，Nanosac将通过其柔软性和对siRNA的封装来克服这些挑战 以及非阳离子的、蛋白基化的表面。为了验证这一假设，我们将追求三个具体目标：(I) 优化用于多基因靶向的纳米囊的设计和生产；(Ii)确定毒性、药代动力学(PK)、 Nanosac的生物分布(BD)和药效学；(Iii)利用Nanosac和 通过图像引导放射治疗肿瘤靶向。这一战略的核心创新是我们开创了 作为核酸载体的无毒、非阳离子、柔软的纳米胶囊，它克服了 传统的基因载体，依靠阳离子电荷进行装载和细胞内传递。因此，我们 不仅有可能克服系统性地将siRNA输送到实体肿瘤的持续挑战 而是打开了一系列其他基因靶向策略的大门。