[Show abstract][Hide abstract] ABSTRACT: The polyanionic nature of oligonucleotides and their enzymatic degradation present challenges for the use of siRNA in research
and therapy; among the most notable of these is clinically relevant delivery into cells. To address this problem, we designed
and synthesized the first members of a new class of guanidinium-rich amphipathic oligocarbonates that noncovalently complex,
deliver, and release siRNA in cells, resulting in robust knockdown of target protein synthesis in vitro as determined using
a dual-reporter system. The organocatalytic oligomerization used to synthesize these co-oligomers is step-economical and broadly
tunable, affording an exceptionally quick strategy to explore chemical space for optimal siRNA delivery in varied applications.
The speed and versatility of this approach and the biodegradability of the designed agents make this an attractive strategy
for biological tool development, imaging, diagnostics, and therapeutic applications.
Proceedings of the National Academy of Sciences 08/2012; 109(33):13171-13176. · 9.81 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Inspired originally by peptides that traverse biological barriers, research on molecular transporters has since identified the key structural requirements that govern cellular entry, leading to new, significantly more effective and more readily available agents. These new drug delivery systems enable or enhance cellular and tissue uptake, can be targeted, and provide numerous additional advantages of significance in imaging, diagnostics and therapy.
Drug Discovery Today Technologies 01/2012; 9(1):e49-e55.
[Show abstract][Hide abstract] ABSTRACT: A new family of guanidinium-rich molecular transporters featuring a novel oligocarbonate backbone with 1,7-side chain spacing is described. Conjugates can be rapidly assembled irrespective of length in a one-step oligomerization strategy that can proceed with concomitant introduction of probes (or by analogy drugs). The new transporters exhibit excellent cellular entry as determined by flow cytometry and fluorescence microscopy, and the functionality of their drug delivery capabilities was confirmed by the delivery of the bioluminescent small molecule probe luciferin and turnover by its intracellular target enzyme.
Journal of the American Chemical Society 11/2009; 131(45):16401-3. · 10.68 Impact Factor