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

项目总结 三阴性乳腺癌(TNBC)的特征是缺乏雌激素/孕激素受体和 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，尤其是对 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 与损伤相关的分子模式(阻尼物)的释放有关。潮湿是一个促成因素 癌症相关炎症可通过几种机制促进未来的转移扩散 如肿瘤转移微环境(TMEM)部位的发展。这些阻尼器包括 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， 具有不同电荷和大小的水溶性树枝状聚合物，取决于其 末端分枝和分枝程度(即世代)。以胺终止的PAMAM是 带正电荷(即阳离子)，能与DNA和RNA结合。在这个树状分子的基础上，我们有 合成毒性降低的第三代阳离子PAMAM-G3衍生物 并且可以将化学制剂包裹成纳米颗粒，并保持其与核酸的结合性能。我们的 初步测试表明，这些材料既可以与无细胞DNA结合，也可以与以 阿霉素、紫杉醇等化疗对三阴性乳腺癌细胞的治疗效果。 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抑制物结合 并压制住。这些材料的抗转移作用将通过体外和体内模型进行研究。 以及病人的血清样本。一种小鼠转移性乳腺癌模型将作为 评价传统化疗与传统化疗的效果 PAMAM-G3纳米粒对原发肿瘤生长、转移程度和炎症的影响 小鼠血清中的材料。综上所述，我们建议追求(1)特征的具体目标 化疗后TNBC细胞释放的损伤相关分子模式(DAMP)； (2)测定PAMAM-G3清除剂和纳米粒对肺癌的治疗效果。 化疗引起的免疫系统激活和侵袭潜能；以及(3) 了解PAMAM-G3介导的湿气清除机制。这里面的实验 该提案将为化疗如何影响循环前体型提供新的知识。 转移性潮湿。此外，一种新的双重化疗给药和清湿方法，通过 将研究修饰的PAMAM-G3纳米粒子在减少原发肿瘤和转移方面的作用 负担。在哥伦比亚大学完成这项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，准备成为一名独立的研究人员。

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.