Systemic delivery of miR-29 for basal-like breast cancer treatment

系统性递送 miR-29 用于基底样乳腺癌治疗

• 批准号: 9177851
• 负责人: Dan Shu
• 金额: $ 21.11万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9177851
• 关键词: Binding; Biodistribution; Biological; Biology; Breast Cancer Cell; Breast Cancer Model; Breast Cancer Treatment; Breast Cancer cell line; Breast Cancer therapy; CD44 gene; Cancer Biology; Cancer Relapse; Cell surface; Cells; Clinical; Data; Development; Disease; Drug Kinetics; Drug Targeting; ERBB2 gene; Epidermal Growth Factor Receptor; Estrogen Receptors; In Vitro; Incidence; Injection of therapeutic agent; MDA MB 231; Malignant Neoplasms; Mammary gland; MicroRNAs; Modeling; Modification; Mus; Nanotechnology; Neoplasm Metastasis; Organ; Population; Positioning Attribute; Progesterone Receptors; Proteins; Publications; RNA; RNA Stability; Recurrent disease; Research; System; Testing; Therapeutic; Tissues; Treatment Efficacy; Tumor Suppressor Proteins; Tumor Tissue; anticancer research; aptamer; cancer therapy; design; functional restoration; hormone therapy; in vivo; malignant breast neoplasm; malignant phenotype; mouse model; multidisciplinary; nanoparticle; novel; novel strategies; novel therapeutics; research study; targeted treatment; therapeutic RNA; therapeutic miRNA; therapeutic target; three dimensional cell culture; tool; tumor; tumor progression

ABSTACT Basal-like breast cancer is estrogen receptor (ER), progesterone receptor (PR) and Her2 negative; it is not responsive to hormone therapy and drugs that target the HER2 protein. Therefore, it is urgent to develop novel therapeutic strategies for basal-like breast cancer. Basal-like breast cancer is rich in tumor-initiating cells. Tumor initiating cells are drivers of cancer metastasis and relapses; thus targeting tumor-initiating cells is critical for basal-like breast cancer treatment. Our recent study shows that 3WJ RNA nanoparticles incorporated with EGFR aptamer successfully bind and enter into the basal-like breast cancer cell line MDA- MB 231 in culture and in the orthotopic mouse mammary tumor model. RNA aptamers targeting the tumor initiating cell marker CD44 have been identified and characterized, which offers a potential strategy for delivering the 3-way junction (3WJ) RNA nanoparticles into tumor initiating cells. We and others recently demonstrate that miR-29b is a potent tumor suppressor for basal-like breast cancer. Expression of exogenous miR-29b in basal-like breast cancer cell lines significantly inhibits cancer metastasis in orthotopic mammary tumor models and repressed malignant phenotypes in 3D culture. MiR-29 also demonstrate potent inhibitory activity on tumor-initiating cells. Therefore, we predict that therapeutic delivery of miR-29b will inhibit basal-like breast cancer progression and metastasis. The overall objective of this proposal is to develop a novel approach to therapeutically deliver tumor suppressor miRNA into basal-like breast cancer. In combining with RNA aptamers to target cell surface markers of basal-like breast cancer and 2’F modification to enhance miRNA stability, the RNA nanoparticle provides a powerful tool to therapeutically deliver miR-29 to basal-like breast cancer. The central hypothesis of this proposal is that tumor suppressor miR-29b can be therapeutically delivered to basal-like breast cancer tissue using 3WJ RNA nanoparticles, and subsequently represses cancer progression and metastasis. To test our central hypothesis and achieve the objective of this proposal, we have designed experiments with the following specific aims. Aim 1. Construct RNA nanoparticles harboring therapeutic miR-29b that will target basal-like breast cancer cells. Aim 2. Examine the biologic activity of multifunctional therapeutic RNA nanoparticles in the orthotopic mouse mammary tumor model. Development of RNA nanoparticles that deliver miR-29b to basal-like breast cancer tissue and tumor-initiating cells will overcome the current hurdle in utilizing miRNA for cancer therapy. Examining the potential of exogenous miR-29b in inhibiting progression and metastasis of basal-like breast cancer may identify a potential therapeutic strategy for this deadly disease.

抽象 基底样乳腺癌是雌激素受体（ER）、孕激素受体（PR）和Her 2阴性的;它是 对激素治疗和靶向HER 2蛋白的药物无反应。因此，迫切需要发展 基底细胞样乳腺癌的新治疗策略。基底样乳腺癌富含肿瘤起始细胞。 肿瘤起始细胞是癌症转移和复发的驱动因素;因此靶向肿瘤起始细胞是治疗癌症的关键。 对于基底样乳腺癌的治疗至关重要。我们最近的研究表明，3 WJ RNA纳米颗粒 与EGFR适体结合后成功进入基底细胞样乳腺癌细胞系MDA-1， MB 231在培养物中和原位小鼠乳腺肿瘤模型中。靶向肿瘤的RNA适体 起始细胞标志物CD 44已被鉴定和表征，这为 将所述三向连接（3 WJ）RNA纳米颗粒递送到肿瘤起始细胞中。我们和其他人最近 证明miR-29 b是基底样乳腺癌的有效肿瘤抑制因子。表达外源 基底细胞样乳腺癌细胞系中的miR-29 b显著抑制原位乳腺癌中的癌症转移 肿瘤模型和抑制恶性表型的3D培养。MiR-29也显示出有效的抑制性。 对肿瘤起始细胞的活性。因此，我们预测miR-29 b的治疗性递送将抑制基底样细胞凋亡。 乳腺癌进展和转移。本提案的总体目标是开发一种新的 将肿瘤抑制miRNA治疗性递送到基底样乳腺癌中的方法。在结合与 靶向基底样乳腺癌细胞表面标志物的RNA适体和增强基底样乳腺癌细胞表面标志物的2 'F修饰 miRNA的稳定性，RNA纳米颗粒提供了一个强大的工具，以治疗性地将miR-29递送到基底样细胞。 乳腺癌这一提议的中心假设是肿瘤抑制因子miR-29 b可以被 使用3 WJ RNA纳米颗粒治疗性递送至基底样乳腺癌组织，并且随后 抑制癌症进展和转移。为了验证我们的中心假设， 根据这一建议，我们设计了具有以下具体目标的实验。目标1。构建RNA 携带治疗性miR-29 b的纳米颗粒将靶向基底样乳腺癌细胞。目标2. 在原位小鼠中检查多功能治疗性RNA纳米颗粒的生物活性 乳腺肿瘤模型开发递送miR-29 b至基底样乳腺癌的RNA纳米颗粒 组织和肿瘤起始细胞将克服目前利用miRNA进行癌症治疗的障碍。 检测外源性miR-29 b抑制基底细胞样乳腺癌进展和转移的潜力 癌症可能为这种致命疾病找到一种潜在的治疗策略。