Cytosine residues influence kidney accumulations of 99mTc-labeled morpholino oligomers.
Watson-Crick pairing between complementary oligomers is proving to be an effective means for rapidly directing radioisotopes specifically to the exterior surface of cancer cells in vivo. In such pretargeting applications, it is highly desirable that the excess of isotopically labeled oligomers, which do not bind to the cancer cells, be rapidly cleared from the body. In this context, understanding the influence of chain length and base sequence of the radiolabeled oligomers is critical. We had earlier determined that the kidneys are the principal targets of short-chain radiolabeled morpholino oligomers (MORFs). To explain these observations, MORFs consisting of uniform cytosines (Cs), uniform thymines (Ts), uniform adenines (As), and uniform AAG repeat were labeled with technetium-99m (99mTc) and studied in normal mice. In a limited investigation of the influence of oligomer backbone, a 20-mer MORF (MORF20) with a base sequence rich in Cs was compared with a phosphoromonothioate DNA (S-DNA20) of the same sequence. The in vivo behavior of the labeled MORFs was nearly identical in all organs, with the exception of kidneys. The kidney accumulations were about 25- to 80-fold higher for the uniform Cs relative to the other three uniform MORFs at 3 hours. The S-DNA20 rich in Cs showed only modest kidney accumulations compared with the equivalent MORF20, presumably because of preferential clearance of the S-DNA20 through the liver. Urine analysis showed no evidence of intact labeled S-DNA20 in contrast to fully intact labeled MORF20. We conclude that the high kidney levels observed by us previously for MORFs are most likely due largely to the C residues in the base sequence. In the case of S-DNAs, this phenomenon is partly disguised by the increased hepatic excretion and degradation. These results show that the base sequences of MORFs, and probably other oligomers as well, are an important determinant of biodistribution.
Liu
Guozheng
G
Division of Nuclear Medicine, Department of Radiology, University of Massachusetts Medical School, Worcester, MA 01655, USA.
He
Jiang
J
Zhang
Surong
S
Liu
Changbin
C
Rusckowski
Mary
M
Hnatowich
Donald J
DJ
D000818:Animals; D002851:Chromatography, High Pressure Liquid; D003596:Cytosine / Q000378:metabolism*; D007275:Injections, Intravenous; D007553:Isotope Labeling; D007668:Kidney / Q000378:metabolism*; D008297:Male; D051379:Mice; D009025:Morpholines / Q000097:blood / Q000737:chemistry* / Q000493:pharmacokinetics* / Q000652:urine; D015609:Organotechnetium Compounds / Q000032:analysis / Q000493:pharmacokinetics; D012680:Sensitivity and Specificity; D013667:Technetium / Q000032:analysis* / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D014018:Tissue Distribution
D009025:Morpholines; D015609:Organotechnetium Compounds; D013667:Technetium; D003596:Cytosine