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.

摘要