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与应用抑制乳腺癌原发灶和转移灶的进展

• 批准号: 10599908
• 负责人: Tolulope Olatokunbo Akinade
• 金额: $ 2.51万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10599908
• 关键词: 4T1; Acute; Adjuvant Chemotherapy; Amines; Binding; Biocompatible Materials; Breast Cancer Cell; Breast Cancer Model; Breast Cancer Patient; Breast Cancer Treatment; Breast cancer metastasis; Cancer Biology; 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; Invaded; Knowledge; Luciferases; Macrophage; 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; Tumor Promotion; 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; 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

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。

项目成果

Drug delivery carriers with therapeutic functions.

• DOI: 10.1016/j.addr.2021.113884
• 发表时间: 2021-09
• 期刊: Advanced drug delivery reviews
• 影响因子: 16.1
• 作者: Cai SS;Li T;Akinade T;Zhu Y;Leong KW
• 通讯作者: Leong KW

Comparative Analysis of Nucleic Acid-Binding Polymers as Potential Anti-Inflammatory Nanocarriers.

• DOI: 10.3390/pharmaceutics16010010
• 发表时间: 2023-12-20
• 期刊: Pharmaceutics
• 影响因子: 5.4
• 作者: Bhansali D;Akinade T;Li T;Zhong Y;Liu F;Huang H;Tu Z;Devey EA;Zhu Y;Jensen DD;Leong KW
• 通讯作者: Leong KW

DAMPs/PAMPs induce monocytic TLR activation and tolerance in COVID-19 patients; nucleic acid binding scavengers can counteract such TLR agonists.

• DOI: 10.1016/j.biomaterials.2022.121393
• 发表时间: 2022-04
• 期刊: Biomaterials
• 影响因子: 14
• 作者: Naqvi I;Giroux N;Olson L;Morrison SA;Llanga T;Akinade TO;Zhu Y;Zhong Y;Bose S;Arvai S;Abramson K;Chen L;Que L;Kraft B;Shen X;Lee J;Leong KW;Nair SK;Sullenger B
• 通讯作者: Sullenger B