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: 7102726
• 负责人: Patrick S. Stayton
• 金额: $ 41.42万
• 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 2008-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7102726
• 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(申请人提供)：我们研究的长期目标是为必须在靶细胞内发挥作用的大分子药物开发新的药物输送系统。生物技术和制药行业已经开发出基于生物分子的各种潜在疗法：DNA、RNA和蛋白质。对于治疗药物，如质粒DNA、反义寡核苷酸、核酶和免疫毒素，它们到达靶点的能力取决于它们从内体间隔到达细胞质的初始能力。虽然这些疗法具有巨大的潜力，但有效地制定和实施它们也是一个被广泛认识的挑战。存在各种困难的障碍，包括药物稳定性、组织渗透和转运。虽然许多创造性的递送系统显示出利用作用于细胞外膜的生物分子来克服这些问题的巨大潜力，但对于那些在细胞内发挥作用的生物分子来说，一个普遍的障碍是细胞质进入。被动的或受体介导的内吞作用导致生物分子定位到内小体隔室，在那里主要的运输命运是与溶酶体融合和随后的降解。同样，基于质粒或基于蛋白质/多肽的分子疫苗的输送也依赖于将质粒送到细胞核，或将多肽或蛋白质送入细胞质，以进入蛋白质加工和展示途径。这项提议旨在开发模拟自然界中发现的高效细胞内递送系统的合成聚合物载体，而不具有病毒和致病系统的免疫原性和危险特性。它们最重要的性质是将对pH变化的感知与膜的不稳定活性联系在一起。因此，“智能”的聚合物载体能够使内体逃逸，并帮助大分子药物运输到细胞质，从而绕过溶酶体运输的命运。载体应该能够有效地提供广泛的生物治疗药物，并开辟攻击细胞内靶点的新候选药物家族。