Controlled Release of Macromolecules

描述（由申请人提供）：这是对高分子量制剂（如蛋白质和核酸）研究的资助更新。在过去的29年里，这个特殊的补助金一直是我们药物输送研究的核心。我们相信我们的NIH资助的研究在这一领域的影响是显着的，我们的工作已经帮助提供了一些必要的基本概念的控制释放的大分子和局部给药的临床开发。此类递送系统的实例是Lupron Depot、Gliadel和Nutropin Depot。在撰写我们最后一个竞争性的更新拨款提案时，我们认为肽和蛋白质释放的大部分基本原理已经建立，最大的影响可能来自于延长我们的研究核酸交付。我们在这一领域的研究已经导致了更大的机械理解，并产生了35篇同行评议的论文，包括在科学和自然等期刊上。基因治疗在临床上取得成功的主要障碍是缺乏安全有效的DNA递送方法。修饰的病毒虽然能有效地将DNA转移到细胞中，但存在严重的毒性和生产问题。相比之下，非病毒系统提供了许多显著的潜在优势，包括易于生产、稳定性、低毒性和减少的载体大小限制。从我们的研究中，我们已经发现，最佳的细胞内递送到体内不同的组织需要不同的材料。因此，我们建议开发新材料的组合文库，其特定目标是产生临床上有用的非病毒基因治疗方法。肺癌将用作模型疾病。我们建议探索两种互补的方法：1）开发用于抗肿瘤治疗的肺肿瘤细胞特异性DNA递送系统和2）通过靶向和激活天然免疫细胞来开发抗肺癌DNA疫苗。我们的具体目标是：1.开发新一代可生物降解聚合物，用作肺癌和DNA疫苗的高效无毒载体。2.肺肿瘤和树突状细胞靶向的细胞特异性DNA递送系统的开发。3.在正常和肺癌小鼠模型中测试由基于PEI和PBAE的聚合物组成的可生物降解载体及其静电配体涂覆的三元聚合复合物的体内基因递送效率。4.研究基于PEI和PBAE的载体作为DNA疫苗的潜力。

DESCRIPTION (provided by applicant): This is a grant renewal for studies on formulations of high molecular weight agents, such as proteins and nucleic acids. For the past 29 years, this particular grant has been central for our drug delivery research. We believe the impact of our NIH funded research in this area has been significant and that our work has helped provide some of the fundamental concepts necessary for the clinical development of controlled release of macromolecules and for localized drug delivery. Examples of such delivery systems are Lupron Depot, Gliadel and Nutropin Depot. In writing our last competing renewal grant proposal we felt that much of the fundamentals of peptide and protein release had been established and that the greatest impact could come from extending our research nucleic acid delivery. Our studies in this area have led to a greater mechanistic understanding, and have resulted in 35 peer-reviewed papers, including in such journals such as Science and Nature. The major barrier to the success of gene therapy in the clinic is the lack of safe and efficient DNA delivery methods. Modified viruses, while effective at transferring DNA to cells, suffer from serious toxicity and production problems. In contrast, non-viral systems offer a number of significant potential advantages, including ease of production, stability, low toxicity, and reduced vector size limitations. From our studies we have discovered that optimal intracellular delivery to different tissues in the body requires different materials. Therefore, we propose to develop combinatorial libraries of new materials with the specific goal of generating clinically useful, non-viral methods for gene therapy. Lung cancer will be used as a model disease. We propose to explore two complementary approaches: 1) developing lung-tumor cell specific DNA delivery systems for the anti-tumor therapy and 2) developing anti-lung cancer DNA vaccines by targeting and activating native immune cells. Our specific aims are: 1. To develop next-generation biodegradable polymers for use as efficient and non-toxic vectors for lung cancer and DNA vaccines. 2. Development of cell specific DNA delivery systems for lung tumor and dendritic cell targeting. 3. To test the in vivo gene delivery efficiency of biodegradable vectors composed of PEI- and PBAE- based polymer and that of their electrostatic ligand coated ternary polyplexes in normal and lung cancer mouse models. 4. To examine potential of PEI- and PBAE- based vectors for their use as DNA vaccines.