siRNA-based Gold Nanoparticles as a Therapeutic Enhancer for Triple Negative Breast Cancer (TNBC) Radiotherapy
siRNA-based Gold Nanoparticles as a Therapeutic Enhancer for Triple Negative Breast Cancer (TNBC) Radiotherapy
批准号:
10729127
负责人:
Branislava Janic
金额:
$7.62万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2023
资助国家:
美国
项目状态:
未结题
起止时间:
2023-07-10 至 2025-06-30
关键词:
AdjuvantAnimalsBreast Cancer CellBreast Cancer ModelBreast Cancer therapyCell SurvivalCellsChemicalsClinicalCombination Drug TherapyCombination immunotherapyDNA DamageDataDrug CarriersDrug Delivery SystemsDyesEnhancersEnvironmentEnzyme-Linked Immunosorbent AssayExhibitsFutureGoalsGrowthImmuneImmune systemImmunologic StimulationImmunosuppressionImmunotherapeutic agentImmunotherapyIn VitroIncubatedInterventionMalignant NeoplasmsMeasuresMicroscopyMolecularMouse Cell LineMusNatureNeoadjuvant TherapyNeoplasm MetastasisOpticsOutcomePathway interactionsPatientsPatternPhenotypePrimary NeoplasmProductionPrognosisPropertyPublic HealthPublishingQuantitative Reverse Transcriptase PCRRNA chemical synthesisRNA deliveryRadiationRadiation therapyRadiation-Sensitizing AgentsRadiosensitizationResearchRoleSmall Interfering RNASurvival RateTestingTherapeuticTherapeutic EffectTherapeutic immunosuppressionTransforming Growth Factor betaTransmission Electron MicroscopyTreatment EfficacyTumor ImmunityTumor TissueTumor-infiltrating immune cellsWorkXenograft Modelanti-canceranti-tumor immune responseantitumor effectcancer cellcancer immunotherapycancer radiation therapycancer typecyanine dye 5cytokinedesignimmune checkpoint blockersimmunogenic cell deathimmunogenicityimmunomodulatory therapiesimmunoregulationimprovedin vivoin vivo optical imaginginnovationinterestmalignant breast neoplasmmouse modelmultimodalitynanoGoldnovel strategiesprospectiveradiation effectrecruitresponsetreatment responsetriple-negative invasive breast carcinomatumortumor growthtumor microenvironmentuptakezeta potential
中文摘要
摘要
放射治疗(RT)调节肿瘤微环境(TME)的免疫学特性,以刺激肿瘤微环境(TME)。
抗肿瘤免疫反应然而,RT也启动免疫抑制机制,因此
减少RT免疫刺激的作用。主要的RT免疫抑制模式之一是通过以下方式发挥作用:
乳腺癌(BC)中TGF β 1产生的增加对已经很高的TGF β 1水平具有累加效应
由癌细胞自身产生。特别是三阴性乳腺癌(TNBC),被证明是
与其他BCs相比,TGF β 1水平更高,这一发现与肿瘤分级增加相关,
侵袭性和患者存活率降低。因此,RT诱导TME内TGF β 1的增加,
可能进一步增强TNBC的侵袭性和转移潜力。由于RT的刺激性方面
免疫调节,RT作为癌症免疫治疗中的一种有前景的治疗增强剂而引起了人们的兴趣,
例如免疫检查点阻断剂,在改善局部控制和总体
在特定癌症中的存活率。不幸的是,在大多数形式的BC中,包括TNBC,
保持谦虚。我们的长期目标是使用RT来增强TNBC对免疫疗法的反应,
RT免疫调节潜力的优势。抗肿瘤RT效应,包括TME免疫调节,可
通过使用放射增敏剂如金纳米颗粒(AuNP)来改善。此外,AuNP还可以用作
通过小干扰RNA(siRNA)缀合的药物递送系统。在这个项目中,我们建议使用
通过TGF β siRNA功能性修饰的AuNPs,以同时增强RT免疫调节和抵消
免疫抑制作用与TGF β 1产生增加有关。这种方法将增强RT
这有助于提高抗肿瘤作用,并为未来的免疫治疗创造有利的TME环境。这
将通过以下具体目的进行测试:目的1:合成和表征AuNP-siRNATGF β 1;目的
2:研究RT与AuNP-siRNATGFβ1联合应用的体内外疗效
小鼠TNBC模型。所提出的确定AuNPs同时靶向
抗肿瘤和免疫调节RT效应将为改善TNBC对
免疫检查点阻断剂和用于设计未来的RT/免疫检查点阻断剂的多模式TNBC
治疗
英文摘要
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-siRNATGF1; 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.
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