Design, Synthesis, and Cellular Delivery of Antibody Targeted, Radiolabelled Oligonucleotide Conjugates for Cancer Therapy

Antisense and antigene oligonucleotides provide an exciting avenue for the potential therapy of many significant diseases including cancer and microbial infection. There are now numerous examples in the literature where antisense oligonucleotides have been used to inhibit efficiently gene expression both in vitro and in vivo (Carter and Lemoine, 1993; Uhlmann and Peyman, 1990). However, before the full potential of these compounds can be realised it will be necessary to overcome many problems, particularly those relating to delivery mechanisms and uptake by cells. Perhaps the principal barrier to effective therapy with antisense or antigene compounds lies in the difficulty with which these polar compounds cross the cell membrane. This results in inefficient localisation of oligonucleotides into the appropriate compartment of the cell. Modified oligonucleotides containing phosphorothioate or methylphosphonate linkages have shown improved potential for use as therapeutic molecules in in vitro models, principally due to increased resistance to serum nucleases and better cell membrane permeation. Unfortunately, they have not become clinically practical owing to the expense of producing the large quantities necessary to achieve the desired effect, and more importantly, the lack of specificity for in vivo delivery to target tissue. Currently, there are no known methods to deliver large quantities of oligonucleotide specifically and efficiently to target cells in vitro or in vivo.