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

多模式混合纳米粒子用于治疗三阴性乳腺癌

基本信息

批准号：
10514997
负责人：
Juan Luis Vivero-Escoto
金额：
$ 45.03万
依托单位：
UNIVERSITY OF NORTH CAROLINA CHARLOTTE
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10514997
关键词：
Address African American Age American Cancer Society Antibodies Apoptotic Award BCL-2 Protein Biological Biology Brain Breast Cancer Patient Cancer Etiology Cessation of life Chemicals Chemistry Chemotherapy and/or radiation Clinical Collaborations Data Development Diagnosis Disease Doxorubicin Drug Delivery Systems ERBB2 gene Environment Ethnic Origin Fiber Formulation Gene Silencing Goals Grant Hispanic Hybrids Immune response Immunologics In Vitro MDA MB 231 Metastatic Neoplasm to the Lung Modality Modeling Mutate Neoplasm Metastasis Operative Surgical Procedures Outcome Outcomes Research PUVA Photochemotherapy Patients Performance Photosensitizing Agents Population Prognosis Property Public Health RNA RNA-targeting therapy Radiation therapy Recurrence Reporting Research Resistance Silicon Dioxide Small Interfering RNA System Technology Testing Therapeutic Therapeutic Effect Therapeutic Studies Training Treatment Efficacy United States Woman Work alternative treatment base brca gene cancer diagnosis career chemotherapy chlorin clinical care combinatorial design effective therapy experience high risk improved in vivo malignant breast neoplasm men mortality multimodality nanocarrier nanoparticle nanoparticulate new therapeutic target novel novel therapeutics nucleic acid delivery nucleic acid-based therapeutics orthotopic breast cancer prevent programs protoporphyrin IX relapse risk side effect targeted delivery therapeutic siRNA therapeutic target triple-negative invasive breast carcinoma tumor tumor heterogeneity undergraduate student

项目摘要

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).

摘要乳腺癌（BC）是女性中最常见的癌症，并且仍然是主要原因之一美国女性癌症相关死亡率。2021年，美国癌症协会估计，女性（281，550）和男性（2，650）诊断出284，200例乳腺癌（BC）新病例，估计有43，600名女性和530名男性死亡。三阴性乳腺癌（TNBC）是BC的一种亚型与年龄较小、非裔美国人和西班牙裔种族背景以及BRCA基因突变相关人口。TNBC缺乏ER/PR/HER 2和有意义的治疗靶点的表达，接受常规化疗和放疗。TNBC的特征在于肿瘤内这些肿瘤具有高度的异质性、高度的增殖活性、不良的预后、高度的复发风险以及肺和脑的转移。大约50%的被诊断患有早期TNBC的患者经历复发，并且37%的患者在24小时内死亡。手术后的前5年。因此，克服化疗耐药性的新的治疗替代方案并防止复发和转移是必不可少的，以显着提高临床护理这一致命的疾病治疗性核酸（TNAs）和光动力疗法（PDT）的显著特征，例如低副作用，针对不同的细胞死亡机制，以及潜在的免疫作用，使这些治疗模式是治疗TNBC的一种有前途的替代方案。在这个项目中，我们正在开发一个使用两种不同的基于二氧化硅的平台的组合方法;聚倍半硅氧烷（PSilQ）和介孔载有光敏剂（二氢卟酚e6（Ce 6））的二氧化硅纳米颗粒（MSNs），以及新的基于纳米颗粒的TNAs（RNA纤维，RNAfs）。我们的目标是抗凋亡蛋白Bcl 2，它是一种相关目标，以改善TNBC的治疗。该项目的主要目标是开发一个多模式的纳米颗粒平台用于TNBC的有效治疗。为了实现这一目标，我们将设计、合成和表征RNAf负载的PEG-Ce 6-PSilQ和RNAf负载的PEG-Ce 6-MSN（目的1）。我们会研究治疗和沉默作用，对该平台体外细胞死亡和免疫应答的影响（目的 2）。从Aim 2获得的结果将使我们能够决定哪一个是在中评估的最佳平台下一个目标最后，我们将研究和验证所选的治疗效果和对转移的影响。系统在TNBC的原位模型中（目标3）。