Design and Application of Cationic Nanocarriers to Inhibit Breast Cancer Progression in Primary and Metastatic Sites

阳离子纳米载体的设计和应用抑制乳腺癌原发灶和转移灶的进展

基本信息

批准号：
10379060
负责人：
Tolulope Olatokunbo Akinade
金额：
$ 4.68万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10379060
关键词：
4T1 Acids Acute Amines Binding Biocompatible Materials Breast Cancer Cell Breast Cancer Model Breast Cancer Patient Breast Cancer Treatment Breast cancer metastasis Cancer Biology Cations Cell Death Cells Charge Control Groups DNA Binding Data Dendrimers Development Diagnosis Disease Doxorubicin Electrostatics Encapsulated Engineering Epidermal Growth Factor Receptor Estrogens Excision Future Generations HMGB1 gene Human Immune Immune system In Vitro Inbred BALB C Mice Inflammation Inflammatory Inflammatory Response Infusion procedures Institutional Review Boards Interleukin-6 Knowledge Luciferases Malignant Neoplasms Measures Mediating Medicine Metastatic breast cancer Methods MicroRNAs Mitotic Modeling Molecular Mus NF-kappa B Necrosis Neoadjuvant Therapy Neoplasm Metastasis Nucleic Acid Binding Nucleic Acids Operative Surgical Procedures Organ Paclitaxel Pathway interactions Patients Pattern Polymers Preparation Primary Neoplasm Progesterone Receptors Property Proteins RNA Receptor Activation Recurrence Research Research Personnel Sampling Serum Site Structure System TNF gene Testing Therapeutic Effect Time Toll-like receptors Toxic effect Training Treatment Efficacy Tumor Cell Invasion Universities Water Woman breast cancer progression cancer diagnosis cancer subtypes cell free DNA chemotherapy cytokine design experimental group experimental study fighting imaging study immune activation improved in vitro Assay in vivo Model macrophage malignant breast neoplasm mammary mortality nanocarrier nanoparticle neoplastic cell novel novel therapeutic intervention protein complex targeted treatment taxane treatment group triple-negative invasive breast carcinoma tumor tumor growth tumor microenvironment

项目摘要

PROJECT SUMMARY Triple-negative breast cancer (TNBC) is characterized by the lack of estrogen/progesterone receptors and human epidermal growth factor receptor 2 (HER2) expression as well as its high rates of recurrence and metastasis. Chemotherapy persists as one of the mainstays of breast cancer treatment, particularly for triple-negative breast cancer. While chemotherapy is beneficial for killing the malignant tumor cells, it leads to the release of damage-associated molecular patterns (DAMPs). DAMPs are a contributing factor to cancer-related inflammation which can potentiate future metastatic spread through several mechanisms such as the development of tumor microenvironments of metastasis (TMEM) sites. These DAMPs include nucleic acids, cytokines, and proteins such as HMGB1. Polyamidoamine (PAMAM) is a biodegradable, water-soluble dendrimer polymer with the ability to possess different charges and sizes depending on its terminal branches and degree of branching (i.e. generation), respectively. Amine-terminated PAMAM is positively charged (i.e. cationic) and can bind DNA and RNA. Building on this dendrimer, we have synthesized modified cationic PAMAM-generation 3 (PAMAM-G3) derivatives that have decreased toxicity and can encapsulate chemodrugs as nanoparticles and maintain the nucleic acid-binding property. Our preliminary tests have shown that these materials can bind to both cell-free DNA and RNA released as a result of treating triple-negative breast cancer cells with chemotherapy such as doxorubicin and paclitaxel. In this research plan we aim to explore what other chemotherapy-induced DAMPs our materials can bind to and suppress. The anti-metastatic effects of the materials will be studied using in-vitro and in-vivo models as well as patient serum samples. A murine metastatic breast cancer model will serve as the basis for assessing the effects of traditional chemotherapy delivery compared with chemotherapy delivery using PAMAM-G3 nanoparticles with respect to primary tumor growth, degree of metastasis, and inflammatory materials in mouse serum. In summary, we propose to pursue the specific aims of (1) Characterize damage-associated molecular patterns (DAMPs) released from chemotherapy-treated TNBC cells; (2) Determine the therapeutic efficacy of PAMAM-G3 scavenging polymers and nanoparticles on immune system activation and invasive-potential caused by chemotherapy-induced DAMPs; and (3) Understand the mechanisms behind PAMAM-G3 mediated DAMP scavenging. The experiments in this proposal will contribute new knowledge on how chemotherapy influences the profile of circulating pro- metastatic DAMPs. In addition, a novel method of dual chemotherapy delivery and DAMP scavenging via modified PAMAM-G3 nanoparticles will be studied for its utility in reducing primary tumor and metastatic burden. Completion of this proposal at Columbia University will provide the applicant with training in cancer biology and engineering in medicine in preparation to becoming an independent investigator.

项目摘要三阴性乳腺癌（TNBC）的特征是缺乏雌激素/孕酮受体和人表皮生长因子受体2（HER2）表达以及其高复发率和转移。化学疗法持续为乳腺癌治疗的主要支柱之一，特别是三阴性乳腺癌。虽然化学疗法有益于杀死恶性肿瘤细胞，但它导致释放损伤相关的分子模式（湿）。潮湿是导致的因素与癌症相关的炎症，可以通过多种机制增强未来转移性扩散例如转移（TMEM）部位的肿瘤微环境的发展。这些潮湿包括核酸，细胞因子和蛋白质（例如HMGB1）。聚酰胺胺（PAMAM）是可生物降解的，水溶性树枝状聚合物聚合物具有不同的电荷和大小的能力，具体取决于其分支的末端分支和程度（即产生）。胺终止的PAMAM是带正电的（即阳离子），可以结合DNA和RNA。在此树枝状聚合物的基础上，我们有合成的修饰阳离子PAMAM生成3（PAMAM-G3）衍生物降低了毒性并可以将化学果作为纳米颗粒封装，并保持核酸结合特性。我们的初步测试表明，这些材料可以与无细胞的DNA和RNA结合为A 用化学疗法（例如阿霉素和紫杉醇）治疗三阴性乳腺癌细胞的结果。在本研究计划中，我们旨在探讨其他化学疗法引起的潮湿，我们的材料可能与并抑制。将使用视野和体内模型研究材料的抗转移效应以及患者血清样品。鼠转移性乳腺癌模型将作为与使用化学疗法的递送相比，评估传统化学疗法递送的影响 PAMAM-G3纳米颗粒相对于原发性肿瘤的生长，转移程度和炎症程度小鼠血清中的材料。总而言之，我们建议追求（1）的特定目的从化学疗法处理的TNBC细胞中释放出与损伤相关的分子模式（潮湿）；（2）确定PAMAM-G3清除聚合物和纳米颗粒的治疗功效由化学疗法诱导的潮湿引起的免疫系统激活和侵入性电势；（3）了解PAMAM-G3介导的潮湿的机制。其中的实验提案将为化学疗法如何影响循环促进疗法的形象有助于新知识。转移性潮湿。此外，一种新型的双重化疗递送和通过将研究改良的PAMAM-G3纳米颗粒，以减少原发性肿瘤和转移性负担。在哥伦比亚大学完成此建议的完成将为申请人提供癌症培训医学领域的生物学和工程，准备成为独立研究者。