Biofunctional Polymers for Intracellular Drug Delivery

用于细胞内药物输送的生物功能聚合物

• 批准号: 6932389
• 负责人: Patrick S. Stayton
• 金额: $ 41.19万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-19 至 2007-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6932389
• 关键词: DNA; acid base balance; antisense nucleic acid; biomaterial development /preparation; biotechnology; chromatography; confocal scanning microscopy; drug delivery systems; drug vehicle; enzyme linked immunosorbent assay; fluorescence microscopy; intracellular transport; laboratory rat; macrophage; membrane activity; nuclear magnetic resonance spectroscopy; oligonucleotides; polymers; tissue /cell culture; western blottings

DESCRIPTION (provided by applicant): The long-term objective of our research is to develop new drug delivery systems for macromolecular drugs that must function inside the target cell. The biotechnology and pharmaceutical industries have developed a wide variety of potential therapeutics based on the molecules of biology: DNA, RNA and proteins. For therapeutics such as plasmid DNA, antisense oligonucleotides, ribozymes, and immunotoxins, their ability to reach their target is dependent on their initial ability to reach the cytoplasm from the endosomal compartment. While these therapeutics have tremendous potential, effectively formulating and delivering them has also been a widely recognized challenge. There are a variety of difficult barriers, including drug stability, tissue penetration and transport. While a number of creative delivery systems show significant potential for overcoming these problems with biomolecules that act at the extracellular membrane, a widespread barrier for those that function intracellularly is cytoplasmic entry. Passive or receptor-mediated endocytosis results in localization of biomolecules to the endosomal compartment, where the predominant trafficking fate is fusion with lysosomes and subsequent degradation. Similarly, the delivery of plasmid-based or protein/peptide based molecular vaccines is also dependent on getting the plasmid to the nucleus, or the peptides or proteins into the cytoplasm for entry into the protein processing and display pathways. This proposal is aimed at developing synthetic polymeric carriers that mimic the highly efficient intracellular delivery systems found in nature, without the immunogenicity and dangerous properties of viral and pathogenic systems. Their most important property ties together the sensing of pH changes to membrane destabilizing activity. The "smart" polymer carriers thus enable endosomal escape and aid the transport of the macromolecular drugs to the cytoplasm, to circumvent the lysosomal trafficking fate. The carriers should enable the efficient delivery of a wide range of biotherapeutics, and open new families of drug candidates that attack intracellular targets.

描述（由申请人提供）：我们研究的长期目的是开发用于必须在目标细胞内部起作用的大分子药物的新药物输送系统。生物技术和制药行业基于生物学分子：DNA，RNA和蛋白质开发了多种潜在的治疗剂。对于治疗剂，例如质粒DNA，反义寡核苷酸，核酶和免疫毒素，它们达到目标的能力取决于其最初从内体隔室达到细胞质的能力。尽管这些治疗学具有巨大的潜力，但有效制定和交付它们也是一个广泛认可的挑战。有多种困难障碍，包括药物稳定性，组织穿透和运输。虽然许多创造性的输送系统在克服这些问题的生物分子上表现出巨大的潜力，这些生物分子在细胞外膜上起作用，但对于细胞内功能的人来说，它是细胞质的广泛障碍。被动或受体介导的内吞作用会导致生物分子定位到内体室中，其中主要的贩运命运是与溶酶体融合的，随后的降解。同样，基于质粒或蛋白质/肽的分子疫苗的递送也取决于将质粒传递到细胞核中，或者将肽或蛋白质或蛋白质或蛋白质转移到细胞质中，以进入蛋白质加工和显示途径。该建议旨在开发合成的聚合物载体，这些载体模仿自然界中发现的高效细胞内递送系统，而没有病毒和致病系统的免疫原性和危险特性。他们最重要的特性将pH的感知变化为膜不稳定活性。因此，“智能”聚合物载体可以使内体逃逸并帮助大分子药物传输到细胞质，从而避免溶酶体贩运命运。携带者应有效地提供广泛的生物治疗药，并开放攻击细胞内靶标的新的候选药物家族。