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.

项目概要三阴性乳腺癌（TNBC）的特点是缺乏雌激素/孕激素受体，人表皮生长因子受体 2 (HER2) 的表达及其高复发率和转移。化疗仍然是乳腺癌治疗的主要手段之一，特别是对于三阴性乳腺癌。虽然化疗有利于杀死恶性肿瘤细胞，但它会导致损伤相关分子模式（DAMP）的释放。 DAMP 是一个促成因素与癌症相关的炎症可以通过多种机制增强未来的转移扩散例如肿瘤转移微环境（TMEM）的发展。这些 DAMP 包括核酸、细胞因子和蛋白质，如 HMGB1。聚酰胺胺 (PAMAM) 是一种可生物降解的、水溶性树枝状聚合物，能够根据其具有不同的电荷和尺寸分别是末端分支和分支程度（即世代）。胺封端的 PAMAM 是带正电荷（即阳离子），可以结合 DNA 和 RNA。在这种树枝状聚合物的基础上，我们有合成了具有降低毒性的改性阳离子 PAMAM 第 3 代 (PAMAM-G3) 衍生物并且可以将化学药物封装为纳米颗粒并保持核酸结合特性。我们的初步测试表明，这些材料可以与游离 DNA 和 RNA 结合，以释放形式释放。用阿霉素和紫杉醇等化疗治疗三阴性乳腺癌细胞的结果。在这项研究计划中，我们的目标是探索我们的材料可以与哪些其他化疗诱导的 DAMP 结合并压制。将使用体外和体内模型研究材料的抗转移作用以及患者血清样本。小鼠转移性乳腺癌模型将作为基础评估传统化疗与化疗相比的效果 PAMAM-G3 纳米颗粒对原发肿瘤生长、转移程度和炎症的影响小鼠血清中的材料。总之，我们建议追求以下具体目标：（1）表征化疗处理的 TNBC 细胞释放的损伤相关分子模式 (DAMP)； (2) 确定 PAMAM-G3 清除聚合物和纳米颗粒对化疗诱导的 DAMP 引起的免疫系统激活和侵袭潜力；和（3）了解 PAMAM-G3 介导的 DAMP 清除背后的机制。本次实验中该提案将贡献关于化疗如何影响循环亲细胞特征的新知识转移性 DAMP。此外，一种通过双化疗递送和 DAMP 清除的新方法将研究修饰的 PAMAM-G3 纳米颗粒在减少原发性肿瘤和转移性肿瘤方面的效用负担。在哥伦比亚大学完成此提案将为申请人提供癌症方面的培训医学生物学和工程学，为成为一名独立研究者做准备。