TISSUE DISTRIBUTION AND METABOLISM OF THE [P-32] LABELED OLIGODEOXYNUCLEOSIDE METHYLPHOSPHONATE-NEOGLYCOPEPTIDE CONJUGATE, YEE(AH-GALNAC)(3)]-SMCC-AET-PU(M)P(T)UNDER-BAR(7), IN THE MOUSE

Development of oligodeoxynucleotides (oligo-dNs) and their analogs as therapeutic agents is complicated by their low rate of transport acros s cellular membranes, which is required for interaction with the intra cellular complementary nucleic acid sequences, and the lack of tissue- specific delivery, To overcome these obstacles, bioconjugates between cell surface receptor ligands and oligodeoxynucleoside methylphosphona tes (oligo-MPs) have been constructed containing homogeneous, chemical ly defined covalent linkages, We have previously established that a mo del conjugate, [P-32]-labeled [YEE(ah-GalNAc)(3)]-SMCC-AET-<pU(m)p(T)u nder bar (7)> (1), is delivered to Hep G2 cells in a ligand-specific m anner, reaching a peak value of 26 pmol per 10(6) cells after 24 hours incubation at 37 degrees C (Hangeland et al., 1995), In this work, th e in vivo behavior of this conjugate is explored, Administration of th is conjugate to mice via. tail vein injection demonstrates rapid uptak e in liver to the extent of 69.9 +/- 9.9% of the injected dose after 1 5 minutes, Thereafter, the conjugate and its metabolites are rapidly c leared via the kidney and urine, Polyacrylamide gel electrophoresis an alysis of extracts of Hep G2 cells and mouse liver reveal the conjugat e 1 to be extensively metabolized, In contrast, the conjugate found in mouse urine is largely intact, These data show that this novel, biode gradable delivery vehicle represents a viable approach for the deliver y of antisense oligo-MPs and other oligo-dN analogs to the liver for t herapeutic and diagnostic applications.