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。虽然其总体治愈率已显着提高，但目前晚期或复发乳腺癌的治愈率低于5%。化疗是与手术和/或放射治疗一起治疗乳腺癌患者的主要策略。然而，化疗受到一些缺点的限制，例如全身毒性和缺乏特异性。基于纳米级颗粒的药物递送代表了更集中地递送此类治疗药物的重大改进。提高药物递送特异性的另一个途径是通过干细胞，干细胞可以作为将治疗性细胞因子靶向肿瘤的递送载体。我们从脐带沃顿氏胶中分离出的干细胞，称为“脐带基质干细胞”（UCMS），也可以选择性地运输到肿瘤。这些 UCMS 细胞可以在出生后从取之不尽用之不竭的来源中大量分离。我们的长期目标是开发一种新的策略，通过将治疗性纳米粒子加载到癌症组织的干细胞中来靶向递送治疗性纳米粒子。为了实现这一目标，设计了实验来在体外和体内测试干细胞/纳米凝胶/治疗剂。在具体目标 1 中，我们将用自杀基因（胸苷激酶）改造 UCMS 细胞，用几种多重纳米凝胶治疗组合装载它们，将它们与乳腺癌细胞共培养，并在添加前药 ganciclivor (GCV) 后释放颗粒。在具体目标 2 中，我们将在转移性人乳腺癌 (MDA-231) 细胞的 SCID 小鼠模型中测试最佳治疗剂-纳米凝胶组合。用于封装蒽醌衍生物 AQ10、三烯双醌 TT24（两者都是由堪萨斯州立大学华博士（共同研究员）开发的有效抗癌小分子）、阿霉素和顺铂等治疗剂的纳米凝胶是聚乙二醇-聚乙烯亚胺（ PEG-PEI)，具有最佳的亚甲基与质子比 (>6:1)。我们将使用干细胞荧光加载（SP-DiI）、免疫细胞化学、蛋白质印迹、干细胞基因工程、细胞凋亡测定和图像分析来实现这些目标。拟议的研究具有创新性、新颖性，并将允许靶向输送强效抗癌小分子药物，这些药物存在溶解度问题或毒副作用，否则会限制其在人类乳腺癌患者中的应用。成功完成拟议的研究后，我们的程序将具有未来转化研究的巨大潜力。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与性别相关的癌症。目前晚期或复发性乳腺癌的治愈率低于5%。尽管化疗是治疗乳腺癌患者的主要策略，但化疗受到全身毒性和缺乏特异性等几个缺点的限制。我们提出的研究的主要目标是通过融合干细胞生物学和基于纳米技术的靶向递送系统，开发一种实用的乳腺癌靶向化疗。我们在此提出的治疗策略明显优于现有的治疗策略，因为我们预计治疗结果会更有效，但副作用会少得多。一旦我们的假设被证明是正确的，这个程序将来将应用于人类患者。因此，这项研究应该对改善公众健康做出重大贡献。