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

摘要 放射治疗(RT)调节肿瘤微环境(TME)的免疫学特性以刺激 抗肿瘤免疫反应。然而，RT也启动了免疫抑制机制，因此 减弱RT免疫刺激的作用。主要的RT免疫抑制模式之一是通过 转化生长因子在乳腺癌(BC)中的增加对已经很高的转化生长因子水平具有相加作用 由癌细胞本身产生。尤其是三重阴性乳腺癌(TNBC)，被证明 与其他BC相比有更高的转化生长因子水平，这一发现与肿瘤分级和 侵袭性和病人存活率降低。因此，RT诱导TME内转化生长因子的增加 可能进一步增强TNBC的侵袭性和转移潜能。由于RT的刺激性方面 免疫调节，RT在癌症免疫治疗中作为一种有前景的治疗增强剂已引起人们的兴趣， 例如免疫检查点阻滞剂，这在改善局部控制和总体上显示出巨大的潜力 部分癌症患者的存活率。不幸的是，在包括TNBC在内的大多数形式的BC中，对免疫治疗的反应 仍然保持谦虚。我们的长期目标是使用RT通过服用以下药物来增强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 通过使用放射增敏剂，如金纳米颗粒(AuNP)进行了改进。此外，AuNPs还可以用作 一种通过小干扰RNA(SiRNA)结合的药物输送系统。在这个项目中，我们建议使用 转化生长因子siRNA修饰AuNPs同时增强RT免疫调节和中和作用 免疫抑制作用与增加转化生长因子的产生有关。这种方法将提高RT 抗肿瘤作用，并创造一个良好的TME环境，以更好地应对未来的免疫疗法。这 将通过以下具体目标进行测试：目标1：合成和表征AuNP-siRNatGF1； 2.观察RT联合AuNP-siRNAGFβ-1的体内外治疗作用 小鼠TNBC模型。确定AuNPs同时靶向潜力的研究进展 抗肿瘤和免疫调节RT效应将为改善TNBC对 免疫检查点阻滞剂和设计未来RT/免疫检查点阻滞剂多模式TNBC 治疗。

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.