ENHANCED TUMOR TARGETING AND IMPROVED ANTITUMOR-ACTIVITY OF DOXORUBICIN BY LONG-CIRCULATING LIPOSOMES CONTAINING AMPHIPATHIC POLY(ETHYLENE GLYCOL)

Enhanced delivery of doxorubicin (DXR) to colon 26 in mice was studied by the long-circulating liposomes (LCL) composed of distearoylphospha tidylcholine cholesterol (DSPC CH) (1 1. m m) and 6 mol% distearoyl ph osphatidyl ethanolamine (DSPE) derivatives of poly(ethylene glycol) (P EG) with an average molecular weight of 1000. LCL was approximately 10 0 nm in mean diameter and encapsulated DXR with > 98% entrapping effic iency by the transmembrane pH gradient method. The control liposomes ( LP) which had the same lipid composition, similar size and DXR entrapm ent as LCL. but did not have amphipathic PEG. were used for comparison . Liposomal DXR and free DXR were injected intravenously at a dose of 5 mg DXR kg to Balb c mice implanted subcutaneously with colon 26 carc inoma. DXR encapsulated in LCL showed high blood levels up to 24 h aft er injection. compared with the corresponding DXR-LP and free DXR. The value of the area under the curve (AUG) of blood was approximately 2. 4-or 810-fold higher than that of DXR-LP or free DXR. respectively. LC L decreased the uptake amount of DXR by the reticuloendothelial system (RES) of liver and spleen. Both liposomal formulations effectively re duced the DXR concentrations in heart compared with free DXR. Compared with DXR-LP or free drug, DXR-LCL produced an approximately 3.6-or 10 .5-fold increased DXR level in tumor, respectively. at 6 h after injec tion. The AUC value of tumor tissue for DXR-LCL was 3.4-or 9.4-fold hi gher than that of DXR-LP or free DXR, respectively. These high tumor l evels of DXR by LCL corresponded to the prolonged residence feature of liposomes. Therapeutic experiments were performed with three differen t formulations of DXR. Administration of DXR-LCL at a dose of 10 mg DX R kg resulted in effective retardation of tumor growth and 2-fold prol ongation of survival times compared with DXR-LP. free drug and saline. Our results indicate that DXR encapsulated in long-circulating liposo mes is significantly more active against colon 26 carcinoma than the c onventional liposome (DSPC CH, 1:1, m m) formulation of DXR and free d rug. Thus long-circulating liposomes should be useful carriers of chem otherapeutic agents for the treatment of solid tumor.