Guanidinium-rich, glycerol-derived oligocarbonates: a new class of cell-penetrating molecular transporters that complex, deliver, and release siRNA.
A highly versatile and step-economical route to a new class of guanidinium-rich molecular transporters and evaluation of their ability to complex, deliver, and release siRNA are described. These new drug/probe delivery systems are prepared in only two steps, irrespective of length or composition, using an organocatalytic ring-opening co-oligomerization of glycerol-derived cyclic carbonate monomers incorporating either protected guanidine or lipid side chains. The resultant amphipathic co-oligomers are highly effective vehicles for siRNA delivery, providing an excellent level of target protein suppression (>85%). These new oligocarbonates are nontoxic at levels required for cell penetration and can be tuned for particle size. Relative to the previously reported methyl(trimethylene)carbonate (MTC) scaffold, the ether linkage at C2 in the new transporters markedly enhances the stability of the siRNA/co-oligomer complexes. Both hybrid co-oligomers, containing a mixture of glycerol- and MTC-derived monomers, and co-oligomers containing only glycerol monomers are found to provide tunable control over siRNA complex stability. On the basis of a glycerol and CO2 backbone, these new co-oligomers represent a rapidly tunable and biocompatible siRNA delivery system that is highly effective in suppressing target protein synthesis.
['Wender|Paul A|PA|', 'Huttner|Melanie A|MA|', 'Staveness|Daryl|D|', 'Vargas|Jessica R|JR|', 'Xu|Adele F|AF|']
D001702:Biopharmaceutics D002254:Carbonates D002460:Cell Line D002463:Cell Membrane Permeability D016503:Drug Delivery Systems D005990:Glycerol D019791:Guanidine D006801:Humans D034622:RNA Interference D034741:RNA, Small Interfering D000067492:RNAi Therapeutics
oligocarbonates guanidinium-rich molecular transporters siRNA delivery 1,3-glycerol carbonate organocatalytic ring-opening oligomerization