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: 10330483
• 负责人: Stephen J. Kron
• 金额: $ 57.67万
• 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/10330483
• 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.

抽象的 头部和颈癌目前通过伴随的化学疗法和放射线治疗，但局部复发和 转移性疾病仍然是一个问题。特别是，有迫切需要改善高级治疗 中位生存期为6至12个月的转移性头颈部鳞状细胞癌（HNSCC）（HNSCC） 即使进行侵略性化疗，单独或与辐射或靶向剂结合在一起。检查点封锁 已尝试使用抗体的免疫疗法（CBI）仅实现20-30％的缓解率。抵抗 HNSCC中的免疫疗法部分归因于免疫抑制的全面性质 一个检查点的封锁可以通过另一个负调节途径来平衡，瞬态 目标抗体参与的性质，允许快速恢复抑制性信号。考虑到这些挑战， siRNA被认为是基于模块化的抗体增强CBI益处的有前途的替代品 siRNA，可以实现多靶向治疗，以及RNA干扰的潜力提供持久作用。 但是，如果没有可靠肿瘤递送的手段，siRNA将保持不适合CBI和其他目标 癌症疗法。开发可实现有利的生物分布和肿瘤细胞的安全核酸载体 静脉注射的摄取将克服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启用全身基因递送到肿瘤，这是一种新型的软柔软， 非阳离子聚酰胺纳米胶囊，将siRNA固定在里面，并采用了本机白蛋白的电晕 循环。我们通过与siRNA涂层介孔二氧化硅纳米颗粒（MSN），然后与pol- YDOPAMINE，并去除牺牲MSN核心。纳米可提供siRNA和沉默的目标基因 体外毒性，结合白蛋白并容易渗出并渗透到肿瘤中，并抑制肿瘤 作为靶向PD-L1的siRNA的系统性载体。我们的中心假设是阳离子电荷 常规合成基因载体典型的核酸和/或暴露于循环时间 对肿瘤和安全性的涂装，纳米糖会通过其柔软度来克服这些挑战，囊泡的封装 和非阳离子的蛋白基表面。为了检验这一假设，我们将追求三个具体目标：（i） 优化用于多基因靶向的纳米糖的设计和生产； （ii）定义毒性，药代动力学（PK）， 生物分布（BD）和纳米克的药效学； （iii）利用纳米酸的系统性交付和 通过图像引导的辐射靶向肿瘤。这种策略的核心创新是我们已经开创了 纳米酸是一种无毒的，非阳离子的软纳米胶囊，作为核酸载体，它克服了克服的限制 常规的基因载体，依赖于阳离子电荷进行加载和细胞内递送。因此，我们 不仅有潜力克服siRNA向实体瘤的全身递送中的持续挑战 但是，要打开广泛的基因靶向策略的大门。