VOL. 5, No. 1/2, July 2009

M. Rubenstein, et al. [2009] Med. Hypotheses Res. 5: 57‒61.

Antisense Oligonucleotides as Specific
Chemotherapeutic Delivery Agents: A New Type of
Bifunctional Antisense

Marvin Rubenstein*, Paulus Tsui and Patrick Guinan

Division of Cellular Biology, Hektoen Institute for Medical Research, Chicago, IL 60612,
USA (M.R., P.T., P.G.); Departments of Urology (M.R., P.G.) and Biochemistry (M.R.),
Rush University Medical Center, Chicago, IL 60612 USA; Division of Urology, Stroger
Hospital of Cook County, Chicago, IL 60612 USA (M.R., P.T., P.G); and Department of
Urology, University of Illinois at Chicago, Chicago, IL 60612 USA (P.G.)

Abstract. Antisense oligonucleotides (oligos) are linear strands of nucleotide bases
synthesized in a sequence complementary to the protein-encoding mRNAs. These oligos
inhibit the synthesis of specific proteins. In the in vivo and in vitro systems, oligos have
demonstrated efficacy in inhibiting cancer cell growth through targeting protein growth
factors, their receptors, transcription factors, or those that inhibit apoptosis. Since cancer
growth is driven by the over expression of numerous proteins, it is naïve to believe that
inhibition of single proteins would affect a cure, in most cases. Therefore, it is necessary that
many gene products be suppressed. To enhance the efficiency of antisense therapy, oligos
must be developed containing multiple (numerous) binding sites. In initial efforts, bispecific
oligos have been evaluated which target more than one protein. While some of these
bispecifics derive their activity from targeting proteins that share gene sequence homology,
true bispecifics have been described which contain more than one binding site, which do not
share sequence homology, and can target genes from even unrelated pathways. More
complex branched (multispecific) oligos have also been proposed. Here we suggested that the
concept of bispecific oligos should be expanded to include conjugated oligos as delivery
agents. Since oligos have the ability to target only cells which over-express a specific protein,
they also have potential to delivery and concentrate non-covalently bound chemotherapeutic
(and toxic) agents, sparing normal cells from toxicity. Conjugated oligos would have both
the (bispecific) capability for specific drug delivery and sequence specific inhibition.

Correspondence: Dr. Marvin Rubenstein, Division of Cellular Biology, Hektoen
Institute for Medical Research, 2240 W. Ogden Ave., 2nd Floor, Chicago IL 60612, USA.
Tel: 312-864-4621. Fax: 312-348-1935. E-mail: