Crosslinking-based targeted therapy for triple-negative breast cancer

基于交联的三阴性乳腺癌靶向治疗

基本信息

批准号：
10650998
负责人：
Shengxi Chen
金额：
$ 20.29万
依托单位：
ARIZONA STATE UNIVERSITY-TEMPE CAMPUS
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：
2023-04-13 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10650998
关键词：
3-Dimensional Antibodies Antineoplastic Agents Apoptosis Binding Biological Assay Breast Cancer Cell Breast Cancer Patient Breast Cancer Treatment Breast Cancer cell line Breast cancer metastasis Cancer Cell Growth Cause of Death Cell Aggregation Cells Circulation Coupled DNA Disease Distant Metastasis Doxorubicin Drug Delivery Systems Drug Kinetics Drug or chemical Tissue Distribution ERBB3 gene Effectiveness Epidermal Growth Factor Receptor Estrogen Receptors Foundations Goals Growth Hormone Receptor Human In Vitro Inbred BALB C Mice Individual Induction of Apoptosis Innovative Therapy Invaded Mammary Neoplasms Mediating Membrane Metabolic Metastatic Neoplasm to the Lung Metastatic malignant neoplasm to brain Mus Nanostructures Neoplasm Metastasis New Agents Pharmaceutical Preparations Pilot Projects Prevention therapy Primary Neoplasm Progesterone Progesterone Receptors Prognosis Protein Overexpression Reagent Recurrent tumor Resistance Safety Series Site Subgroup Testing Therapeutic Western Blotting Xenograft Model antibody conjugate cancer cell cell motility chemotherapy crosslink design effective therapy in vivo inhibitor innovation malignant breast neoplasm migration mortality mouse model nanoparticle nanoparticle drug novel novel therapeutics overexpression prevent receptor scaffold small molecule targeted agent targeted treatment triple-negative invasive breast carcinoma tumor growth

项目摘要

Abstract The HER1 and/or HER3 receptors are overexpressed in most triple-negative breast cancers (TNBCs), a subtype of breast cancer that lacks estrogen receptor, progesterone, and HER2 expression and is associated with poor prognosis and a high lung and brain metastasis rate. Chemotherapy is the mainstay of TNBC treatment. Our long-term goal is to develop more effective therapy for this aggressive subtype of breast cancer. In this proposal, we aim to develop a novel crosslinking-based targeted therapy. For this purpose, we will create a series of multi-functional DNA-affibody-drug nanoparticles containing multiple copies of HER1 and/or HER3 specific affibody molecules covalently coupled to a DNA nanostructure, of which the latter binds to tens of small molecule drugs such as THZ1. In the presence of these nanoparticles, HER1+ and/or HER3+ TNBC cells will be tightly bound together, thus preventing metastasis in its initial stage. In the cross-linked TNBC cell clusters, the small molecule anticancer agent THZ1 reversibly bound to the nanoparticles will be released slowly, resulting in killing of crosslinked TNBC cells. These nanoparticles can bind to HER1+ and/or HER3+ TNBC cells in primary tumors, metastatic sites, and circulation. In our preliminary study, cultured HER1+ TNBC cells were crosslinked together to form cell clusters with a 96% crosslinking efficiency, 99% migration inhibition, and 90% invasion inhibition by a DNA-4ZHER1-THZ1 nanoparticle (drug-to-cargo ratio is 50). To enhance the efficiency and overcome the resistance to HER1 inhibitors, a novel DNA-2ZHER1-2ZHER3-THZ1 nanoparticle that targets dual HER1 and HER3 will be synthesized and tested in this study. Our design and hypothesis will be tested with the following specific aims: In specific aim 1, we will prepare a DNA-2ZHER1-2ZHER3- drug nanoparticle for targeting HER1- and/or HER3-overexpressing TNBC. In specific aim 2, we will evaluate the inhibition of HER1- and HER3-overexpressing TNBC cell growth and metastasis by the DNA-2ZHER1-2ZHER3- drug nanoparticle in vitro. In specific aim 3, we will study distribution and pharmacokinetics of selected DNA- 2ZHER1-2ZHER3-drug nanoparticle in healthy mice, and to evaluate its suppression of mammary tumor growth and metastasis in TNBC xenograft models. If successful, this innovative approach will open a new avenue for developing new therapy for treatment of TNBC. The pilot study will lay a foundation for further studies to investigate the utilities and mechanisms of the new class of anticancer agents for targeted therapy.

抽象的 HER1 和/或 HER3 受体在大多数三阴性乳腺癌 (TNBC) 中过度表达，缺乏雌激素受体、孕激素和 HER2 表达且与乳腺癌相关的乳腺癌亚型预后差，肺、脑转移率高。化疗是TNBC治疗的主要手段。我们的长期目标是为这种侵袭性乳腺癌亚型开发更有效的治疗方法。在这个根据建议，我们的目标是开发一种新型的基于交联的靶向疗法。为此，我们将创建一个含有多个 HER1 和/或 HER3 拷贝的多功能 DNA 亲和体药物纳米颗粒系列特定的亲和体分子与 DNA 纳米结构共价偶联，后者与数十个小分子结合分子药物如THZ1。在这些纳米颗粒存在的情况下，HER1+ 和/或 HER3+ TNBC 细胞将被紧密地结合在一起，从而在初始阶段防止转移。在交联的 TNBC 细胞簇中，可逆地与纳米颗粒结合的小分子抗癌剂 THZ1 会缓慢释放，从而产生杀死交联的 TNBC 细胞。这些纳米颗粒可以与原代细胞中的 HER1+ 和/或 HER3+ TNBC 细胞结合肿瘤、转移部位和循环。在我们的初步研究中，培养的 HER1+ TNBC 细胞被交联共同形成细胞簇，交联效率为 96%，迁移抑制率为 99%，侵袭率为 90% DNA-4ZHER1-THZ1 纳米颗粒的抑制（药物与货物的比率为 50）。为了提高效率并克服对 HER1 抑制剂的耐药性，新型 DNA-2ZHER1-2ZHER3-THZ1 本研究将合成并测试针对双重 HER1 和 HER3 的纳米颗粒。我们的设计和假设将通过以下具体目标进行检验：在具体目标 1 中，我们将准备 DNA-2ZHER1-2ZHER3- 用于靶向 HER1 和/或 HER3 过表达 TNBC 的药物纳米颗粒。在具体目标 2 中，我们将评估 DNA-2ZHER1-2ZHER3- 抑制 HER1 和 HER3 过表达的 TNBC 细胞生长和转移体外药物纳米颗粒。在具体目标 3 中，我们将研究选定 DNA 的分布和药代动力学 2ZHER1-2ZHER3-药物纳米颗粒在健康小鼠体内的作用，并评估其对乳腺肿瘤生长的抑制作用 TNBC 异种移植模型中的转移。如果成功，这种创新方法将为开发新疗法开辟新途径 TNBC。该试点研究将为进一步研究该方法的效用和机制奠定基础。用于靶向治疗的新型抗癌药物。