Journal
MOLECULAR PHARMACEUTICS
Volume 12, Issue 3, Pages 742-750Publisher
AMER CHEMICAL SOC
DOI: 10.1021/mp500581r
Keywords
guanidinium-rich molecular transporters; siRNA delivery; organocatalytic ring-opening oligomerization; oligocarbonates; 1,3-glycerol carbonate
Funding
- National Institutes of Health [NIH-CA031841, NIH-CA031845]
- National Science Foundation
- Stanford-NIH Training Program in Biotechnology
- Amgen Graduate Research Fellowship
- Stanford Chemistry Undergraduate Summer Research Fellowship
- Chemical Engineering Undergraduate Summer Research Program
- NIH Shared Instrumentation Grant [S10RR027431-01]
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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 C-2 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.
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