Biofunctional Polymers for Intracellular Drug Delivery

描述（由申请人提供）：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递送系统。生物技术和制药工业已经开发出基于生物分子（DNA、RNA和蛋白质）的各种潜在疗法。对于治疗剂如质粒DNA、反义寡核苷酸、核酶和免疫毒素，它们到达其靶标的能力取决于它们从内体区室到达细胞质的初始能力。虽然这些治疗剂具有巨大的潜力，但有效地配制和递送它们也是一个公认的挑战。存在各种困难的屏障，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克服这些问题的显著潜力，但作用于细胞外膜的生物分子的广泛屏障是细胞质进入。被动或受体介导的内吞作用导致生物分子定位于内体区室，其中主要的运输命运是与溶酶体融合和随后的降解。类似地，基于质粒或基于蛋白质/肽的分子疫苗的递送也依赖于使质粒到达细胞核，或使肽或蛋白质进入细胞质以进入蛋白质加工和展示途径。该提案旨在开发合成聚合物载体，其模拟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。它们最重要的特性将pH变化的传感与膜去稳定活性联系在一起。因此，“智能”聚合物载体能够使内体逃逸并帮助大分子药物转运至细胞质，以规避溶酶体转运命运。载体应该能够有效地递送广泛的生物治疗剂，并打开攻击细胞内靶点的候选药物的新家族。

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.