Biofunctional Polymers for Intracellular Drug Delivery

描述（由申请人提供）：我们研究的长期目标是开发必须在靶细胞内起作用的大分子药物的新药物传递系统。生物技术和制药行业已经开发出多种基于生物学分子的潜在治疗方法：DNA、RNA和蛋白质。对于质粒DNA、反义寡核苷酸、核酶和免疫毒素等治疗药物，它们到达目标的能力取决于它们从内体室到达细胞质的初始能力。虽然这些疗法具有巨大的潜力，但有效地制定和提供它们也是一项公认的挑战。有各种各样的困难障碍，包括药物稳定性，组织渗透和运输。虽然许多创造性的递送系统显示出克服这些问题的巨大潜力，这些问题是通过作用于细胞膜外的生物分子来解决的，但对于那些在细胞内起作用的生物分子来说，细胞质进入是一个普遍的障碍。被动或受体介导的内吞作用导致生物分子定位于内体腔室，其中主要的运输命运是与溶酶体融合并随后降解。同样，基于质粒或基于蛋白质/肽的分子疫苗的递送也依赖于将质粒送入细胞核，或将肽或蛋白质送入细胞质以进入蛋白质加工和展示途径。该建议旨在开发合成聚合物载体，模仿自然界中发现的高效细胞内传递系统，而没有病毒和致病系统的免疫原性和危险特性。它们最重要的特性是将pH值变化的感知与膜的不稳定活性联系在一起。因此，“智能”聚合物载体使内体逃逸，并帮助大分子药物运输到细胞质，以避免溶酶体运输的命运。载体应该能够有效地递送各种生物治疗药物，并开辟新的候选药物家族，攻击细胞内靶标。

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.