Poryspermine Imidazole-4,5-imine, a Chemically Dynamic and Biologically Responsive Carrier System for Intracellular Delivery of siRNA

摘要

The ability of small interfering RNA (siRNA), a polynucleotide approximately 21-23 nucleotides in length, to inhibit the expression of target genes has offered scientists new methods to develop customizable medicines.Recent advances in siRNA research have resulted in solutions to multi-target and off-target problems of siRNA.The lack of a safe and efficient synthetic carrier system has become the sole remaining barrier to bringing this revolutionary finding to practical therapeutic technology.A therapeutically feasible synthetic carrier of siRNA should be able to accomplish these five sequential tasks: A) packing siRNA tightly into nano-particulate forms to avoid degradation prior to phagocytosis, B) adsorbing selectively onto diseased cells, C) rupturing the endosomes to facilitate endosomal escape of siRNA, D) releasing siRNA into the cytoplasm, and E) becoming metabolized into nontoxic and eliminable species. Among these five tasks, (A), (C), (D), and (E) may be achieved with a rationally designed polycationic carrier system, because these four steps are universal for all cell types. Herein, we report a multifunctional, yet structurally simple, cationic polymer, polyspermine imidazole-4,5-imine (PSI), which accomplishes these four tasks.