Development of 'Smart' Particles for Enhanced Intracellular Delivery of Therapeutic Nucleic Acids

摘要

Recent advances in drug design have led to the development of several classes of nucleic acid molecules such as plasmid DNA (pDNA), antisense oligodeoxynucleotides (ASODN), short interfering RNA (siRNA), and micro RNA (miRNA), which can be used for treatment of cancer, viral infection, cardiovascular and neurodegenerative diseases [1, 2]. However, cellular uptake of these macromolecules occurs by endocytosis where they accumulate in the endosomal/lysosomal trafficking pathway, which leads to their degradation and loss of therapeutic activity [3, 4]. Several research groups have focused on the development of "smart" pH-sensitive polymers that can effectively shuttle a large dose of therapeutic nucleic acids past the endosomal membrane and into the cytoplasm of targeted cells to achieve the desired therapeutic activity. However, these pH-sensitive polymers are non-degradable and have limited nucleic acid loading capacity. We report the design, synthesis, and in vitro evaluation of new biodegradable, comb-like, pH-sensitive, membrane-destabilizing polymers that enhance the intracellular delivery of nucleic acids into target cells.