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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.

摘要