CELL AND TISSUE DISTRIBUTION OF SYNTHETIC OLIGONUCLEOTIDES IN HEALTHYAND TUMOR-BEARING NUDE-MICE - AN AUTORADIOGRAPHIC, IMMUNOHISTOLOGICAL, AND DIRECT FLUORESCENCE MICROSCOPY STUDY

Antisense oligonucleotides have the ability to inhibit individual gene gene expression in the potential treatment of cancer and viral diseas es. However, the way parenterally administered oligonucleotides distri bute themselves into healthy tissues or tumors is poorly understood In this study, the cell and tissue distribution of two modified or unmod ified phosphodiester pentadeca-beta-oligonucleotides intravenously adm inistered to healthy or tumor-bearing nude mice was assessed by autora diography as we!ell as by dir ect fluorescence and immunoenzymatic his tological methods. Resistance of oligonucleotides to degradation bu nu clease activity was previously studied in vitro. Using these methods w e were able to show the following: 1) within minutes, oligonucleotides permeate all cells and tissues with the exceptions of erythrocytes an d intervertebral discs; 2) cell and tissue distribution does not depen d on the sequence of the given oligonucleotide; 3) concentration of ol igonucleotides is higher within the connective tissue cells than in th e interstitial matrix; 4) after uptake, oligomers partition throughout all of the cellular compartments, including at the highest intracellu lar concentrations in the nuclei; 5) oligonucleotides penetrate easily the tumor cell compartments, oligonucleotide diffusion being unimpede d by the extracellular matrix.