Biodistribution and metabolism of a mixed backbone oligonucleotide (GEM 231) following single and multiple dose administration in mice

Biodistribution and metabolism of a mixed backbone oligonucleotide (MBO), G EM 231, targeted to the RI alpha subunit of protein kinase A has been studi ed in normal and tumor xenografted mice. The study has been carried out usi ng [S-35]-labeled MBO following single and multiple administrations of dose s varying from 2 to 50 mg/kg. MBO showed wide tissue distribution following intravenous and subcutaneous administration. The highest concentration of MBO was in the kidney and liver. The general disposition of MBO was followe d by digitized autoradiographic pictures of tumored mice and further confir med wide tissue disposition and also showed defined intratumor uptake of MB O. Multiple dose administration showed increased disposition in the majorit y of the tissues/organs, with the exception of the kidneys. Analysis of the extracted MBO by polyacrylamide gel electrophoresis (PAGE) showed the pres ence of primarily intact MBO along with its degraded forms. Based on our ra dioactivity levels, the primary route of excretion was in urine, analysis o f which showed mainly degraded forms of MBO.