DEVELOPMENT OF A CELL-BASED NANOFORMULATED ANTI-TUMOR THERAPY

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 靶向疾病部位的基于细胞的药物递送系统的使用可能会彻底改变医疗保健行业。这种基于细胞的药物制剂尚处于起步阶段，但已显示出“概念证明”。 吸附在颗粒表面并截留在细胞内的药物可以溶解在颗粒基质中。基于细胞的纳米配制药物递送系统（如本文开发的那些）可用于治疗和诊断广泛的疾病，包括癌症和神经退行性病症。该提案将开发纳米制剂，可以包装到巨噬细胞中，并在实验室和人类疾病的动物模型中递送到脑肿瘤部位。我们的药物递送系统的基础是骨髓或单核细胞衍生的巨噬细胞（BMM和MDM）。这些细胞将被用作药物载体。由于脑肿瘤诱导神经炎症反应，包括趋化因子梯度的发展，这种生物反应导致单核细胞-巨噬细胞吸引到患病的脑区域。我们认为，BMM或MDM招募到脑疾病的领域可以改善治疗结果，通过提高脑转移率和/或疗效。重要的是，我们基于细胞的递送可以改善错误分布并减少化疗诱导的神经毒性。该项目的基础是最近开发的动物模型系统，用于监测原发性人类脑肿瘤的生物学，免疫和生理学效应。我们将利用我们的内布拉斯加纳米医学中心（NCN）的基础设施来开发集成的成像，病理学和肿瘤生物学平台，以研究如何在细胞中提供抗肿瘤治疗，以最佳方式用于治疗恶性脑肿瘤。该项目旨在在实验室和动物模型研究中测试不同的纳米制剂，并充分利用NCN内的核心结构。总之，这些研究应该能够更好地了解抗肿瘤药物如何最有效地改善疾病结局。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The use of Cell-based drug delivery systems that target disease sites may revolutionize the health care industry. Such cell-based-drug-formulations are in their infancy but have shown "proof of concept". Drugs that are absorbed onto a particle surface and entrapped inside a cell can be dissolved within a particle matrix. Cell-based nanoformulated drug delivery system like those developed herein may be used for treatments and diagnosis of a broad range of diseases including cancer and neurodegenerative disorders. The proposal will develop nanoformulations that can be packaged into macrophages and be delivered to brain tumor sites in laboratory and animal models of human disease. The basis of our drug delivery system is bone marrow or monocyte-derived macrophages (BMM and MDM). These cells will be used as drug carriers. As neuroinflammatory responses are induced by brain tumors including the development of a chemokine gradient, this biological response leads to monocyte-macrophage attraction to diseased brain regions. We posit that BMM or MDM recruited into areas of brain disease can improve therapeutic outcomes by enhancing brain penetrance and/or efficacy. Importantly, our cell-based delivery can improve misdistribution and reduce chemotherapy-induced neurotoxicity. The foundation on which this project is built are recently developed animal model systems that monitor the biologic, immune and physiologic effects of primary human brain tumors. We will utilize an infrastructure of our Nebraska Center for Nanomedicine (NCN) to develop integrated imaging, pathology, and tumor biology platforms to investigate how anti-tumor therapies delivered in cells may be optimally utilized in treatments for malignant brain tumors. The project is designed to test divergent nanoformulations in both laboratory and animal model studies and takes full advantage of the core structures within the NCN. All together, the studies should permit a better understanding of how anti-neoplastic drugs can be effectively most effectively to improve disease outcomes.