siRNA-based Gold Nanoparticles as a Therapeutic Enhancer for Triple Negative Breast Cancer (TNBC) Radiotherapy

基于 siRNA 的金纳米颗粒作为三阴性乳腺癌 (TNBC) 放射治疗的治疗增强剂

• 批准号: 10729127
• 负责人: Branislava Janic
• 金额: $ 7.62万
• 依托单位: HENRY FORD HEALTH SYSTEM
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-10 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10729127
• 关键词: Adjuvant; Animals; Breast Cancer Cell; Breast Cancer Model; Breast Cancer therapy; Cell Survival; Cells; Chemicals; Clinical; Combination Drug Therapy; Combination immunotherapy; DNA Damage; Data; Drug Carriers; Drug Delivery Systems; Dyes; Enhancers; Environment; Enzyme-Linked Immunosorbent Assay; Exhibits; Future; Goals; Growth; Immune; Immune system; Immunologic Stimulation; Immunosuppression; Immunotherapeutic agent; Immunotherapy; In Vitro; Incubated; Intervention; Malignant Neoplasms; Measures; Microscopy; Molecular; Mouse Cell Line; Mus; Nature; Neoadjuvant Therapy; Neoplasm Metastasis; Optics; Outcome; Pathway interactions; Patients; Pattern; Phenotype; Primary Neoplasm; Production; Prognosis; Property; Public Health; Publishing; Quantitative Reverse Transcriptase PCR; RNA chemical synthesis; RNA delivery; Radiation; Radiation therapy; Radiation-Sensitizing Agents; Radiosensitization; Research; Role; Small Interfering RNA; Survival Rate; Testing; Therapeutic; Therapeutic Effect; Therapeutic immunosuppression; Transforming Growth Factor beta; Transmission Electron Microscopy; Treatment Efficacy; Tumor Immunity; Tumor Tissue; Tumor-infiltrating immune cells; Work; Xenograft Model; anti-cancer; anti-tumor immune response; antitumor effect; cancer cell; cancer immunotherapy; cancer radiation therapy; cancer type; cyanine dye 5; cytokine; design; immune checkpoint blockers; immunogenic cell death; immunogenicity; immunomodulatory therapies; immunoregulation; improved; in vivo; in vivo optical imaging; innovation; interest; malignant breast neoplasm; mouse model; multimodality; nanoGold; novel strategies; prospective; radiation effect; recruit; response; treatment response; triple-negative invasive breast carcinoma; tumor; tumor growth; tumor microenvironment; uptake; zeta potential

ABSTRACT Radiation therapy (RT) modulates immunological properties of tumor microenvironment (TME) to stimulate antitumor immune response. However, RT initiates immunosuppressive mechanisms as well and therefore diminishing the effects of RT immuno-stimulation. One of the main RT immunosuppressive modes is exerted by an increase in TGF production that in breast cancers (BC) has an additive effect on already high TGF levels produced by cancer cells themselves. Triple negative breast cancer (TNBC) in particular, was demonstrated to have higher TGF levels compared to other BCs, and this finding correlated with increased tumor grade and invasiveness, and a diminished patient survival. Consequently, RT induced increase in TGF within the TME may further potentiate invasiveness and metastatic potential of TNBC. Due to stimulatory aspects of RT immunomodulation, RT has gained interest as a prospective therapeutic enhancer in cancer immunotherapy, such as immune checkpoint blockers, that has shown great potential in improving local control and overall survival in select cancers. Unfortunately, in most forms of BC, including TNBC, response to immunotherapy remains modest. Our long-term goal is to use RT to enhance TNBC response to immunotherapy by taking advantage of RT immunomodulatory potential. Antitumor RT effects, including TME immunomodulation can be improved by using radiosensitizers, such as gold nanoparticles (AuNP). Furthermore, AuNPs can also serve as a drug delivery system by conjugation of small interfering RNAs (siRNAs). In this project we propose to use AuNPs functionally modified by TGF siRNA to simultaneously enhance RT immunomodulation and counteract the immunosuppressive effects related to the increased TGF production. This approach will enhance RT antitumor effects and create a favorable TME environment for better response to future immunotherapies. This will be tested by the following specific aims: Aim 1: To synthesize and characterize AuNP-siRNATGF1; Aim 2: To investigate the therapeutic effect of combination of RT and AuNP-siRNATGFβ1 in in vitro and in vivo mouse TNBC model. The proposed studies in determining the potential of AuNPs simultaneously target antitumor and immunomodulatory RT effects will provide critical information for improving TNBC response to immune checkpoint blockers and for designing future RT/ immune checkpoint blockers multimodal TNBC therapies.

抽象的 放射治疗 (RT) 调节肿瘤微环境 (TME) 的免疫特性以刺激 抗肿瘤免疫反应。然而，放疗也会启动免疫抑制机制，因此 减少 RT 免疫刺激的影响。主要的 RT 免疫抑制模式之一是通过 乳腺癌 (BC) 中 TGF 产量的增加对已经很高的 TGF 水平产生累加效应 由癌细胞本身产生。特别是三阴性乳腺癌 (TNBC)，已被证明可以 与其他 BC 相比，TGF 水平较高，这一发现与肿瘤分级和肿瘤分级增加相关 侵袭性和患者生存率降低。因此，RT 诱导 TME 内 TGF 增加 可能进一步增强 TNBC 的侵袭性和转移潜力。由于放疗的刺激作用 免疫调节，RT 作为癌症免疫治疗的潜在治疗增强剂引起了人们的兴趣， 例如免疫检查点阻断剂，在改善局部控制和整体控制方面显示出巨大潜力 某些癌症的生存率。不幸的是，在大多数形式的 BC 中，包括 TNBC，对免疫治疗的反应 保持谦虚。我们的长期目标是通过放疗来增强 TNBC 对免疫治疗的反应 RT 免疫调节潜力的优势。抗肿瘤 RT 作用，包括 TME 免疫调节，可以 通过使用放射增敏剂（例如金纳米颗粒（AuNP））可以改善这种情况。此外，AuNPs还可以作为 通过缀合小干扰 RNA (siRNA) 的药物输送系统。在这个项目中我们建议使用 通过 TGF siRNA 功能修饰的 AuNPs 可同时增强 RT 免疫调节和抵消 与 TGFβ 产生增加相关的免疫抑制作用。这种方法将增强 RT 抗肿瘤作用并创造有利的 TME 环境，以便更好地响应未来的免疫疗法。这 将通过以下具体目标进行测试： 目标1：合成并表征AuNP-siRNATGF1；目的 2：研究RT与AuNP-siRNATGFβ1联合的体外和体内治疗效果 小鼠TNBC模型。确定 AuNPs 同时靶向的潜力的拟议研究 抗肿瘤和免疫调节 RT 效应将为改善 TNBC 反应提供关键信息 免疫检查点阻断剂以及用于设计未来 RT/免疫检查点阻断剂多模式 TNBC 疗法。