Liposomal Sustained-Release Delivery Systems for Intravenous Injection. II. : Design of Liposome Carriers and Blood Disposition of Lipophilic Mitomycin C Prodrug-Bearing Liposomes

Various types of unilamellar liposomes possessing a narrow size distribution were prepared by controlled dialysis and their blood clearance was studied in mice and rats to assess their suitability as drug carriers for intravenously injectable liposomal sustained-release delivery systems. Also, the utility of these liposomal carrier systems combined with lipophilic prodrugs of mitomycin C (MMC) was evaluated. The fate of the liposomes was monitored uisng N-4-nitrobenzo-2-oxa-1, 3-diazole-dipalmitoylphosphatidylethanolamine (NBD-PE), a liposomal membrane marker. The effect of vesicle size on the blood clearance was investigated for neutral liposomes. Small-sized (S-) liposomes (90±15 nm) were cleared slowly compared with medium-sized (M-) liposomes (181±31 nm) and large-sized liposomes (281±38 nm). Surface charge was also an important determinant of the disposition of small-sized liposomes. S-Liposomes were retained in the circulation longer than positively (S+-) and negatively (S--) charged liposomes. The integrity of S-liposomes in the circulation was examined by simultaneous determination of NBD-PE and carboxyfluorescein (CF) entrapped in the liposomal membrane and liposomal aqueous phase, respectively. CF administered in the liposome-encapsulated form was cleared slowly in a fashion similar to NBD-PE, while free CF, administered as an aqueous solution, was rapidly removed from the circulation. These results reveal that S-liposomes show the best pharmacokinetic properties as a carrier vehicle for intravenously injectable sustained-release delivery systems. S-Liposomes loaded with the lipophilic MMC prodrug, N-(cholesteryloxycarbonyl)glycyl MMC or cholesteryloxyacetyl MMC, successfully gave sustained blood levels of the parent drug following intravenous injection. Thus, the potential utility of MMC prodrug-bearing S-liposomes as an intravenously injectable MMC sustained-release dosage form was demonstrated.