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

基本信息

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
项目类别：
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

项目摘要

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) 的免疫特性以刺激然而，RT 也会启动免疫抑制机制，因此减少 RT 免疫刺激的影响是主要的 RT 免疫抑制模式之一。乳腺癌 (BC) 中 TGF 产量的增加对已经很高的 TGF 水平产生累加效应尤其是由癌细胞本身产生的三阴性乳腺癌（TNBC）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的增加和侵袭性和患者生存率降低，RT 导致 TME 内 TGF 增加。由于 RT 的刺激作用，可能会进一步增强 TNBC 的侵袭性和转移潜力。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不幸的是，在大多数形式的 BC 中，包括 TNBC，对免疫治疗有反应。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 免疫调节潜力的优点 RT 的抗肿瘤作用，包括 TME 免疫调节。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，AuNP 也可以用作放射增敏剂。在这个项目中，我们建议使用一种通过缀合小干扰 RNA (siRNA) 的药物输送系统。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将增强 RT。抗肿瘤作用并创造有利的 TME 环境，以更好地应对未来的免疫疗法。将通过以下具体目标进行测试：目标1：合成并表征AuNP-siRNATGF1； 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 同时靶向潜力的研究。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。