DRUG AND GENE DELIVERY USING POLYMERS AND LIPOSOMES

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。本研究的目的是利用多肽、聚合物或脂质体将其内容物输送到细胞质中，并对其转运机制进行表征，并利用内切体或溶酶体的低pH环境来催化聚合物/脂质体内容物进入细胞质。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进佐剂。一种方法是合成新型的多肽脂或多肽聚合物，它们可以经历低pH诱导的构象变化，导致引发膜融合的疏水序列的暴露。在本应用中，该多肽将附着在聚合物或脂质体的表面。第二种方法是合成可以进行pH依赖或酶修饰的前体药物，允许它们从溶酶体隔室排出。在这两种应用中，化学和物理方法都被用来设计更有效的药物输送系统，并确定其使用的限制。我们还在开发能够附着到细胞分子马达上的多肽，以将药物或基因引导到特定的位置，如细胞中的细胞核。

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.