Organ selective delivery using a tissue-directed sreptavidin-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 w ith increased TNP substitution, was first observed at 2-3 h: increased to 4 0-50% 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 s ubstitution of other proteins such as bovine serum albumin (BSA) or ovalbum in (Ova) led to a transient short-term liver uptake. The enzyme-resistance property of streptavidin and its biotin binding sites render TNP-modified s treptavidin a potential targeting vehicle to the liver. 5-Fluorouridine (FU R) was attached to high molecular weight carrier carboxymethyldextran (CMde x, derived from 40 kDa dextran) and the dextran-FUR conjugate was charged w ith 2-4 biotinyl groups (in the form of biotinyldiaminopropionyl-tyrosine, BDT) for complexing to TNP-St. Biodistribution monitoring of the BDT-CMdex- FUR ligand, radio labeled at the tyrosyl residue of BDT and targeted via no n-radiolabeled TNP-St, showed that ligand accumulation in the liver was sim ilar to TNP-St itself. Liver targeting of FUR was demonstrated by trace-lab eling FUR with its structural analog 5,6-[H-3] uridine prior to conjugation to dextran hydrazide. Specific liver accumulation of [H-3] radioactivity o ccurred following administration of the conjugate only when complexed to TN P-St. Hepatic levels of [H-3] radioactivity were in the range of 25%/g or 3 5% per whole liver during a period of at least 8 h, as compared to the rapi d elimination of free FUR+[H-3]uridine (4%/g at 20 min). [H-3]-drug radioac tivity disappeared at a faster rate as compared to (125)-I-dextran radioact ivity, suggesting that metabolic processes required to generate the 5,6[H-3 ]uracil-containing active metabolites took place.