Multimodal hybrid nanoparticles for the treatment of triple-negative breast cancer

摘要 乳腺癌(BC)是女性最常见的确诊癌症，至今仍是主要致癌原因之一。 美国女性与癌症相关的死亡率。2021年，美国癌症协会估计 女性(281,550例)和男性(2,650例)新诊断乳腺癌病例284,200例，其中 估计有43,600名女性和530名男性死亡。三阴性乳腺癌(TNBC)是BC的一个亚型 与年轻、非裔美国人和西班牙裔背景以及BRCA基因突变有关 人口。TNBC缺乏ER/PR/HER2的表达和有意义的治疗靶点 接受常规化疗和放射治疗。TNBC的特点是肿瘤内 异质性，高增殖活性，预后差，复发风险高，并转移到肺和脑。 大约50%被诊断为早期TNBC的患者经历了复发，37%的患者在 术后前5年。因此，克服化疗耐药性的新的治疗方案 而预防复发和转移是显著改善这种致命疾病临床护理的关键 疾病。治疗性核酸(TNAS)和光动力疗法(PDT)的显著特点 低副作用，针对不同的细胞死亡机制，以及潜在的免疫效应使这些 治疗方式是治疗TNBC的一种很有前途的选择.在这个项目中，我们正在开发一种 使用两种不同硅基平台的组合方法：聚倍半硅氧烷(PSilQ)和介孔 携带光敏剂(氯化物e6(Ce6))的二氧化硅纳米颗粒(MSN)以及新型 基于纳米颗粒的TNAs(RNA纤维，RNAfs)。我们的目标是抗凋亡蛋白Bcl2，它是一种 相关目标，提高TNBC的治疗水平。该项目的主要目标是开发多式联运 用于有效治疗TNBC的纳米颗粒平台。为了实现这一目标，我们将设计、综合和 表征RNAfs负载的PEG-Ce6-PSilQ和RNAfs负载的PEG-Ce6-MSN(目标1)。我们会研究 体外治疗和沉默作用、对细胞死亡和免疫反应的影响(目的 2)。从目标2获得的结果将使我们能够决定哪个平台是在 下一个目标。最后，我们将调查和验证对选定的转移瘤的治疗效果和效果 TnBC原位模型中的系统(目标3)。

Abstract Breast cancer (BC) is the most frequently diagnosed cancer in women and remains one of the leading causes of cancer-related mortality of women in the United States. In 2021, the American Cancer Society estimated that 284,200 new cases of breast cancer (BC) were diagnosed for both women (281,550) and men (2,650), with an estimated death of 43,600 women and 530 men. Triple-negative breast cancer (TNBC) is a subtype of BC associated with younger age, African American and Hispanic ethnicity background, and BRCA gene-mutated populations. TNBC lacks expressions of ER/PR/HER2 and meaningful therapeutic targets, patients with TNBC are treated with conventional chemotherapy and radiation therapy. TNBC is characterized by intra-tumor heterogeneities, high proliferative activity, poor prognosis, high risk of relapse, and metastasis to lungs and brain. Approximately 50% of the patients diagnosed with early-stage TNBC experience recurrence, and 37% die within the first 5 years after surgery. Therefore, novel therapeutic alternatives to overcome resistance to chemotherapy and to prevent recurrence and metastasis are essential to significantly improve the clinical care of this deadly disease. The remarkable features of therapeutic nucleic acids (TNAs) and photodynamic therapy (PDT) such as low side-effects, targeting different cellular death mechanisms, and potential immunological effects make these treatment modalities a promising alternative for the treatment of TNBC. In this project, we are developing a combinational approach using two different silica-based platforms; polysilsesquioxane (PSilQ) and mesoporous silica nanoparticles (MSNs) carrying a photosensitizing agent (chlorin e6 (Ce6)), together with novel nanoparticle-based TNAs (RNA fibers, RNAfs). We are targeting the anti-apoptotic protein Bcl2, which is a relevant target to improve the treatment of TNBC. The main goal of this project is to develop a multimodal nanoparticulate platform for the efficient treatment of TNBC. To achieve this goal we will design, synthesize and characterize RNAfs-loaded PEG-Ce6-PSilQ and RNAfs-loaded PEG-Ce6-MSNs (Aim 1). We will study the therapeutic and silencing effect, impact on the cellular death and immune response of this platforms in vitro (Aim 2). The results obtained from Aim 2 will allow us to decide which one is the best platform to be evaluated in the next Aim. Finally, we will investigate and validate the therapeutic efficacy and effect on metastasis the selected system in an orthotopic model of TNBC (Aim 3).