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

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

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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.

抽象的在大多数三阴性乳腺癌（TNBC）中，HER1和/或HER3受体过表达缺乏雌激素受体，孕酮和HER2表达的乳腺癌的亚型预后不良，肺和脑转移率高。化学疗法是TNBC治疗的中流疗法。我们的长期目标是为这种激进的乳腺癌亚型开发更有效的治疗方法。在这个提案，我们旨在开发一种新型的基于交联的靶向疗法。为此，我们将创建一个一系列多功能DNA - 附属纳米颗粒，其中包含HER1和/或HER3的多个副本特定的掺杂分子共价耦合到DNA纳米结构，后者结合了几十小的小分子药物，例如THZ1。在存在这些纳米颗粒的情况下，HER1+和/或HER3+ TNBC细胞将是紧密结合在一起，从而阻止转移在其初始阶段。在交联的TNBC细胞簇中小分子抗癌剂Thz1可逆地结合到纳米颗粒，将缓慢释放，从而导致杀死交联的TNBC细胞。这些纳米颗粒可以与初级中的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细胞交联共同形成96％的交联效率，99％迁移抑制和90％入侵的细胞簇 DNA-4ZHEH1-THZ1纳米颗粒抑制（药物与碳酸含量为50）。为了提高效率并克服对HER1抑制剂的抗性，一种新型的DNA-2ZHEH1-2ZHEH3-THZ1 在本研究中，将合成和测试针对双HER1和HER3的纳米颗粒。我们的设计和假设将以以下特定目的进行检验：在特定目标1中，我们将准备DNA-2ZHEH1-2ZHEH3-- 用于靶向HER1和/或过表达HER3的TNBC的药物纳米颗粒。在特定目标2中，我们将评估抑制HER1-和HER3过表达的TNBC细胞生长和DNA-2ZHEHER1-2ZHEHR3-的转移药物纳米颗粒体外。在特定的目标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中，并评估其抑制乳腺肿瘤生长和 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的新途径开放 TNBC。试点研究将奠定进一步研究的基础，以研究研究的实用程序和机制用于靶向治疗的新型抗癌药。