Organ selective delivery using a tissue-directed streptavidin--biotin system: targeting 5-fluorouridine via TNP-streptavidin.
Trinitrophenyl (TNP) modification of streptavidin (St) resulted in high and prolonged accumulation in mouse liver following intravenous administration of radioiodinated TNP streptavidin (TNP-St). Uptake, which is correlated with increased TNP substitution, was first observed at 2-3 h, increased to 40-50% of injected dose/gram tissue (%/g) at 24 h and slowly declined later on. A low degree of accumulation (10%/g) was observed in the spleen. TNP substitution of other proteins such as bovine serum albumin (BSA) or ovalbumin (Ova) led to a transient short-term liver uptake. The enzyme-resistance property of streptavidin and its biotin binding sites render TNP-modified streptavidin a potential targeting vehicle to the liver. 5-Fluorouridine (FUR) was attached to high molecular weight carrier carboxymethyldextran (CMdex, derived from 40 kDa dextran) and the dextran FUR conjugate was charged with 2-4 biotinyl groups (in the form of biotinyl-diaminopropionyl-tyrosine, BDT) for complexing to TNP-St. Biodistribution monitoring of the BDT-CMdex-FUR ligand, radiolabeled at the tyrosyl residue of BDT and targeted via non-radiolabeled TNP-St, showed that ligand accumulation in the liver was similar to TNP-St itself. Liver targeting of FUR was demonstrated by trace-labeling FUR with its structural analog 5,6-[3H]uridine prior to conjugation to dextran hydrazide. Specific liver accumulation of [3H] radioactivity occurred following administration of the conjugate only when complexed to TNP-St. Hepatic levels of [3H] radioactivity were in the range of 25%/g or 35% per whole liver during a period of at least 8 h, as compared to the rapid elimination of free FUR+[3H]uridine (4%/g at 20 min). [3H]-drug radioactivity disappeared at a faster rate as compared to 125I-dextran radioactivity, suggesting that metabolic processes required to generate the 5,6-[3H]uracil-containing active metabolites took place.
Schechter
B
B
Department of Immunology, The Weizmann Institute of Science, Rehovot, Israel.
Chen
L
L
Arnon
R
R
Wilchek
M
M
D000818:Animals; D001665:Binding Sites; D001710:Biotin; D002417:Cattle; D003911:Dextrans / Q000493:pharmacokinetics; D008099:Liver / Q000378:metabolism*; D051379:Mice; D009928:Organ Specificity / Q000187:drug effects; D010047:Ovalbumin / Q000737:chemistry; D012710:Serum Albumin, Bovine / Q000737:chemistry; D013154:Spleen / Q000378:metabolism*; D019809:Streptavidin / Q000493:pharmacokinetics*; D013997:Time Factors; D014529:Uridine / Q000008:administration & dosage / Q000031:analogs & derivatives*
D003911:Dextrans; D012710:Serum Albumin, Bovine; C001943:5-fluorouridine; D001710:Biotin; D010047:Ovalbumin; D019809:Streptavidin; D014529:Uridine