DRUG AND GENE DELIVERY USING POLYMERS AND LIPOSOMES

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。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。所列机构为中心，不一定是研究者所在机构。本研究的目的是使用肽、聚合物或脂质体将其内容物递送到细胞的细胞质中，表征递送机制，并利用内体或溶酶体的低pH环境来催化聚合物/脂质体内容物递送到细胞质中。这项研究的另一个目标是开发治疗癌症的基因和药物方法。我们研究的第三个目标是开发用于人类疫苗的改良佐剂。一种方法是合成新的肽脂质或肽聚合物，其可以经历低pH诱导的构象变化，导致引发膜融合的疏水序列的暴露。在本申请中，肽将连接到聚合物或脂质体的表面。第二种方法是合成前药，所述前药可以经历pH依赖性或酶促修饰，这允许它们从溶酶体区室流出。在这些应用中的任一个中，化学和物理方法被用于设计更有效的药物递送系统并确定其使用的限制。我们还在开发肽，它可以附着在细胞分子马达上，将药物或基因引导到细胞核等特定位置。

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 goal of this research is to use peptides, polymers or liposomes to deliver their contents into the cytoplasm of cells, to characterize the mechanism of delivery and to exploit the low pH environment of the endosome or lysosome to catalyze delivery of polymer/liposomal contents into cytoplasm. Another goal of this research is to develop gene and drug approaches to treat cancer. A third goal of our research is to develop improved adjuvants to use in human vaccines. One approach is to synthesize novel peptide lipids or peptide polymers that can undergo a low pH induced conformational change that results in the exposure of hydrophobic sequences that initiate membrane fusion. The peptide would be attached to the surface of the polymer or liposome in this application. A second approach is to synthesize prodrugs that can undergo either a pH dependent or enzymatic modification which permits their efflux from the lysosomal compartment. In either of these applications chemical and physical approaches are being used to design more efficient drug delivery systems and to determine the limitations to their use. We are also developing peptides that can attach to cellular molecular motors to direct the drug or gene to particular locations such as the nucleus in the cell.