T. Miyao et al., STABILITY AND PHARMACOKINETIC CHARACTERISTICS OF OLIGONUCLEOTIDES MODIFIED AT TERMINAL LINKAGES IN MICE, Antisense research and development, 5(2), 1995, pp. 115-121
Citations number
40
Categorie Soggetti
Medicine, Research & Experimental","Biothechnology & Applied Migrobiology
To construct the strategy for delivery systems that can control in viv
o disposition of antisense oligonucleotides, we studied the stability
and basic pharmacokinetic characteristics of oligonucleotides. Decathy
midylic acid (T-10), a model oligodeoxynucleotide, and its derivatives
, 5'-biotin-T-10 (5'B-T-10) and 3'-methoxyetyethyiam 5'-biotin-T-10 (3
'M5'B-T-10), containing phosphoroamidate modification at 3'- and/or 5'
-terminal internucleoside linkages, were synthesized. In phosphate-buf
fered saline (PBS, pH 7.4) containing 10% mouse serum, unmodified T-10
was degraded with a half-life of 45 minutes; the degradation half-liv
es of 5'B-T-10 and 3'M5'B-T-10 were 11 and 30 h, respectively. In mous
e whole blood, 3'M5'B-T-10 was relatively stable, and 45% remained int
act after 1 h incubation. After intravenous injection of [H-3]3'M5'B-T
-10 into mice at a dose of 1 mg/kg, the radioactivity was rapidly clea
red from plasma with a half-life of 2 minutes and accumulated in the k
idney, liver, and gallbladder. About 30% of the dose was excreted in t
he urine within 60 :minutes. A much more rapid degradation of [H-3]3'M
5'B-T-10 was observed in vivo than expected from in vitro experiments:
more than 90% of the radioactivity in plasma was degradation product
at 2 minutes after injection. These results suggested that enzymatic d
egradation occurred in some compartments in addition to tile blood poo
l. The apparent urinary excretion clearance of [H-3]3'M5'B-T-10 was cl
ose to that of inulin, when!as the apparent hepatic uptake clearance w
as much greater than that of inulin and comparable to that of dextran
sulfate, which is taken up by the liver by scavenger receptors for pol
yanions. Thus, the present study demonstrated that the disposition pro
cesses to be controlled involve stability, urinary excretion, and hepa
tic uptake for the development of oligonucleotide delivery systems.