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p. 8-13 / Oligos & Peptides
Targeted delivery of nucleic acids via carbohydrate-protein interactions
A. STEWART CAMPBELL
Corden Pharma International, Inc., 1-B Gill Street, Woburn, MA 01801, USA

KEYWORDS: Carbohydrate, receptor, nucleic acid drug, targeting, delivery, siRNA.
ABSTRACT:
Nucleic acid drugs are emerging into the pharmaceutical mainstream, but realization of their full potential still requires overcoming technical challenges related to delivery and targeting to the relevant cell types.  Carbohydrate-protein interactions are ubiquitous in mammalian cell systems and offer a promising approach to achieving targeted delivery. In particular, exploitation of cell surface endocytic receptors that bind carbohydrate ligands can lead to efficient cellular uptake of nucleic acid drug cargo. Cell selectivity requires incorporation of rationally designed, synthetic carbohydrates into delivery vehicles, examples of which are the focus of this review.



INTRODUCTION
The pharmaceutical and biotechnology industries are on the cusp of making oligonucleotide drugs a mainstream reality.  From antisense to more recent approaches such as siRNA, miRNA, shRNA and triplex-forming oligonucleotides (TFOs) (1), never before have there been as many candidates in clinical development targeting so many different diseases (Table 1).  What may at first glance appear as a “sudden surge” in the number of candidates in clinical trials, in reality it reflects the culmination of staggering efforts in research over the past 25 years.  Indeed the simple premise that administration of sequence-specific oligonucleotides can treat or even cure disease by altering gene function and regulation was met with an equally complicated and challenging set of technical hurdles that prevented broad-based translation of this concept from bench to bedside. Apart from improvements in our understanding of the biology and pharmacology of gene regulation, recent advances in oligonucleotide chemistry, formulation and drug delivery technologies have combined to overcome many of the practical hurdles, resulting in an ever-increasing number and range of promising therapies in development.

Using a hypothetical siRNA drug as an illustrative example (Figure 1), the functional output of gene silencing is realized only when the siRNA reaches its intracellular target, the mRNA to be silenced; however, the poor pharmacokinetic properties of oligonucleotides make them unsuitable as drugs (2, 3). En route to its target, the negatively charged siRNA must be resistant to destruction by nucleases (stability), cross the negatively charged target cell membrane (cellular uptake), be ushered into the right intracellular compartment (release), be incorporated into the RNA-induced silencing complex (RISC) and finally interfere with the disease-related mRNA (silencing) (4). Success in each of these steps, and particularly in the steps leading up to the silencing event, has been achieved through development and implementation of entirely new technologies or by adapting existing drug delivery technologies to nucleic acid drugs (5).

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