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: 10547820
• 负责人: Stephen J. Kron
• 金额: $ 57.7万
• 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/10547820
• 关键词: Adopted; Albumins; Antibodies; Binding; Biodistribution; Biological; Blocking Antibodies; CD47 gene; Cessation of life; Characteristics; Charge; Chemotherapy and/or radiation; Circulation; Clinic; Development; Diagnosis; Disease; Drug Delivery Systems; Drug Kinetics; Encapsulated; Environment; Extravasation; Formulation; Future; Gene Delivery; Gene Targeting; Genes; Goals; Head and Neck Cancer; Head and Neck Squamous Cell Carcinoma; Image; Imaging Device; Immune; Immunosuppression; Immunotherapy; In Vitro; Malignant Neoplasms; Mediating; Metastatic/Recurrent; Methods; Mission; Modeling; Nature; Nucleic Acids; Nucleosome Core Particle; Oral cavity; Oropharyngeal; Penetration; Permeability; Pharmacodynamics; Porosity; Production; Public Health; RNA Interference; Radiation; Recovery; 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; 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; nucleic acid delivery; prevent; programmed cell death ligand 1; response; siRNA delivery; standard of care; success; targeted agent; targeted cancer therapy; targeted imaging; targeted treatment; 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.

抽象的 头颈癌目前通过同步化疗和放疗进行治疗，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，迫切需要改善晚期晚期患者的治疗 以及转移性头颈鳞状细胞癌 (HNSCC)，其中位生存期为 6 至 12 个月， 即使单独使用积极的化疗，或与放疗或靶向药物联合使用。检查站封锁 使用抗体的免疫疗法 (CBI) 已尝试仅达到 20-30% 的缓解率。抵抗力 HNSCC 的免疫治疗部分归因于免疫抑制的综合性质，其中 一个检查点的封锁可以通过另一种负调节途径来抵消，并且短暂的 靶标抗体结合的性质，允许抑制信号的快速恢复。鉴于这些挑战， 基于模块化，siRNA 被认为是抗体的有前途的替代品，可增强 CBI 的优势 siRNA，实现多靶点治疗，以及 RNA 干扰提供持久效果的潜力。 然而，如果没有可靠的肿瘤递送手段，siRNA 仍将在 CBI 和其他靶向药物中处于边缘地位。 癌症疗法。开发一种安全的核酸载体，实现良好的生物分布和肿瘤细胞 静脉注射吸收将克服 siRNA 疗法临床转化的关键障碍 在癌症中。 本研究的目的是利用 Nanosac（一种新型软、 非阳离子聚多巴胺纳米胶囊，内部装有 siRNA，并采用天然白蛋白的冠层 循环。我们通过用 siRNA 涂覆介孔二氧化硅纳米颗粒 (MSN)，然后用 pol- ydopamine，并去除牺牲的 MSN 核心。 Nanocore 提供 siRNA 并沉默靶基因，无需 体外毒性，与白蛋白结合，易外渗、渗透入肿瘤，抑制肿瘤 生长为靶向 PD-L1 的 siRNA 的系统载体。我们的中心假设是，虽然阳离子电荷 和/或常规合成基因载体典型核酸的暴露会损害循环时间、去 Nanosac 将通过其柔软性、siRNA 封装来克服这些挑战 和非阳离子白蛋白化表面。为了检验这一假设，我们将追求三个具体目标：(i) 优化 Nanosac 的设计和生产以实现多基因靶向； (ii) 定义毒性、药代动力学 (PK)、 Nanosac 的生物分布（BD）和药效学； (iii) 利用 Nanosac 的系统性递送和 通过图像引导辐射进行肿瘤靶向治疗。这一战略的核心创新在于我们开创了 Nanosac，一种无毒、非阳离子、软纳米胶囊作为核酸载体，克服了现有技术的局限性 传统的基因载体，依靠阳离子电荷进行装载和细胞内递送。从而，我们 不仅有潜力克服 siRNA 全身递送至实体瘤的持续挑战 但为广泛的其他基因靶向策略打开了大门。