Stem cells as vehicles for therapeutic nanoparticle delivery to breast cancer

干细胞作为治疗性纳米粒子递送乳腺癌的载体

• 批准号: 7512696
• 负责人: DERYL LEE TROYER
• 金额: $ 19.45万
• 依托单位: KANSAS STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-05-01 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7512696
• 关键词: 9,10-anthraquinone; Address; Adverse effects; Anthraquinones; Antineoplastic Agents; Apoptosis; Attenuated; Biological Assay; Biological Availability; Bone Marrow; Breast Cancer Cell; Breast Cancer Treatment; Breast Carcinoma; Cancer Patient; Cancer cell line; Cells; Cellular biology; Chemicals; Cisplatin; Coculture Techniques; Data; Development; Drug Delivery Systems; Drug resistance; Encapsulated; Engineering; Future; Ganciclovir; Gender; Genes; Genetic Engineering; Goals; Growth; Home environment; Human; Image Analysis; Immune response; In Vitro; Interferon-beta; Kansas; Liver; Lung; Malignant Neoplasms; Mammary Neoplasms; Mediating; Mixed Lymphocyte Culture Test; Mus; NanoGel; Nanotechnology; Neoplasm Metastasis; Numbers; Operative Surgical Procedures; Outcome; Patients; Pharmaceutical Preparations; Polyethylene Glycols; Procedures; Prodrugs; Protons; Public Health; Publishing; Radiation therapy; Rate; Reporting; Research; Research Personnel; SCID Mice; Site; Solubility; Source; Specificity; Stem cells; Strategic Planning; Surface; System; Testing; Therapeutic; Therapeutic Agents; Thymidine Kinase; Tissues; Toxic effect; Umbilical cord structure; United States; Universities; Western Blotting; Wharton' s jelly; Woman; Work; anti-cancer therapeutic; attenuation; base; carbene; chemotherapy; cytokine; cytotoxic; design; immunocytochemistry; improved; in vivo; innovation; lymph nodes; malignant breast neoplasm; mouse model; nanoparticle; nanoscale; novel; novel strategies; particle; prenatal; research study; small molecule; stem; suicide gene; targeted delivery; therapeutic target; trafficking; translational study; trend; tumor; tumor growth

DESCRIPTION (provided by applicant): Breast cancer is the most frequent cancer in women in the United States. Although its overall cure rate has been significantly improved, the current cure rate of advanced or recurring breast cancer is below 5%. Chemotherapy is a major strategy to treat breast cancer patients along with surgery and/or radiation therapy. However, chemotherapy is limited by several drawbacks such as systemic toxicity and lack of specificity. Nano- scale particle-based delivery of drugs represents a major improvement for more focused delivery of such therapeutic drugs. Another avenue for increasing the specificity of drug delivery is via stem cells that can serve as delivery vehicles for targeting therapeutic cytokines to tumors. Stem cells we have isolated from the Wharton's jelly of umbilical cord, termed `umbilical cord matrix stem' (UCMS) cells can also traffic selectively to tumors. These UCMS cells can be isolated in large numbers postnatally from an inexhaustible source. Our long term goal is to develop a novel strategy for targeted delivery of therapeutic nanoparticles by loading them into stem cells that home to cancer tissues. To address this goal, experiments are designed to test the stem cell/nanogel/therapeutic agent in vitro and in vivo. In specific aim 1, we will engineer UCMS cells with a suicide gene (thymidine kinase), load them with several multiple nanogel therapeutic combinations, coculture them with breast cancer cells, and release the particles after addition of the pro-drug ganciclivor (GCV). In specific aim 2, we will test the optimal therapeutic agent-nanogel combination in a SCID mouse model of metastatic human breast carcinoma (MDA-231) cells. The nanogel utilized to encapsulate therapeutic agents such as the anthraquinone derivative AQ10, tryptycene bisquinone TT24 (both are potent anticancer small molecules developed by Dr. Hua (co- investigator) at Kansas State University), Doxorubricin, and Cisplatin is polyethylene glycol- polyethylenimine (PEG-PEI), with an optimal methylene to proton ratio (>6:1). We will use fluorescent loading (SP-DiI) of stem cells, immunocytochemistry, Western blotting, genetic engineering of stem cells, apoptosis assays and image analysis to address these aims. The proposed research is innovative, novel, and will allow targeted delivery of potent anti-cancer small molecule drugs that have solubility issues or toxic side effects that otherwise limit their utility for human breast cancer patients. Upon successful completion of the proposed study, our procedure will have a high potential for future translational study. Therefore, the proposed work is designed to advance the strategic plan outlined in PAR-07-271. Breast cancer is the most common gender-associated cancer in the United States. The current cure rate of advanced or recurring breast cancer is below 5%. Although chemotherapy is the major strategy to treat breast cancer patients, chemotherapy is limited by several drawbacks such as systemic toxicity and lack of specificity. The primary objective of our proposed research is to develop a practical cancer-targeted chemotherapy for breast cancer by merging stem cell biology and a nanotechnology- based targeted-delivery system. Our treatment strategy proposed here is significantly better than existing therapeutic strategies since we anticipate more efficient therapeutic outcome but much fewer side effects. Once our hypothesis is proven correct, this procedure will be applied to human patients in the future. Therefore, this study should significantly contribute to improve public health.

描述（由申请人提供）：乳腺癌是美国女性最常见的癌症。尽管其总体治愈率已显着提高，但目前的晚期或重复乳腺癌的治愈率低于5％。化学疗法是治疗乳腺癌患者以及手术和/或放射疗法的主要策略。但是，化学疗法受到多种缺点，例如全身毒性和缺乏特异性。基于纳米尺度的药物递送代表了这种治疗药物更集中递送的重大改进。提高药物递送特异性的另一个途径是通过干细胞作为将治疗性细胞因子靶向肿瘤的递送车。干细胞我们已经从沃顿酒店的脐带果冻中分离出来，称为“脐带基质茎”（UCMS）细胞也可以选择地传输到肿瘤。这些UCMS细胞可以在未取之不尽的来源中大量分离。我们的长期目标是通过将其加载到癌症组织的干细胞中，制定一种新的策略来靶向治疗性纳米颗粒。为了解决这一目标，实验旨在在体外和体内测试干细胞/纳米凝胶/治疗剂。在特定的目标1中，我们将使用自杀基因（胸苷激酶）来设计UCMS细胞，将它们加载到多个纳米凝胶治疗组合，与乳腺癌细胞共培养，并在添加Pro-Drug Ganciclivor（GCV）后释放颗粒。在特定目标2中，我们将在转移性人体乳腺癌（MDA-231）细胞的SCID小鼠模型中测试最佳治疗剂纳米凝胶组合。用来封装治疗剂的纳米凝胶，例如蒽醌衍生物AQ10，丁香烯双喹酮TT24（两者都是Hua博士（堪萨斯州立大学）开发的抗癌小分子，堪萨斯州立大学），堪萨斯州立大学，多克氨基氨基氨基氨基氨基氨基氨基氨基氨基氨基氨基氨基氨基氨基氨基酯（pe）。具有最佳的亚甲基与质子比（> 6：1）。我们将使用干细胞的荧光负荷（SP-DII），免疫细胞化学，蛋白质印迹，干细胞的基因工程，凋亡分析和图像分析来解决这些目标。拟议的研究是创新的，新颖的，并且将允许有效的抗癌小分子药物有针对性地输送溶解性问题或有毒副作用，否则这些药物否则会限制其对人类乳腺癌患者的效用。成功完成拟议的研究后，我们的程序将对以后的翻译研究具有很高的潜力。因此，拟议的工作旨在推进PAR-07-271中概述的战略计划。乳腺癌是美国最常见的性别相关癌症。当前的晚期或重复乳腺癌的治愈率低于5％。尽管化学疗法是治疗乳腺癌患者的主要策略，但化学疗法受到多种缺点，例如全身毒性和缺乏特异性的限制。我们拟议的研究的主要目的是通过合并干细胞生物学和基于纳米技术的靶向分娩系统来开发以癌症为癌症的实用化学疗法。我们在这里提出的治疗策略要比现有的治疗策略要好得多，因为我们预计会更有效的治疗结果，但副作用却更少。一旦我们的假设被证明正确，将来将对人类患者应用此过程。因此，这项研究应该显着有助于改善公共卫生。