Role of drug release and liposome-mediated drug delivery in governing the therapeutic activity of liposomal mitoxantrone used to treat human A431 andLS180 solid tumors

A previous study suggested that drug release is the dominating factor contr olling biological activity of liposomal mitoxantrone in tissues where the r ate of liposome accumulation is rapid. The studies described here attempted to address the question: under conditions where the rate of liposome accum ulation is slow, does drug release or liposome-mediated drug delivery becom e the dominant factor controlling therapeutic activity? Liposomal mitoxantr one formulations exhibiting different drug-release characteristics were inj ected i.v. in mice bearing human carcinoma xenografts: A431 human squamous cell carcinoma and LS180 human colon cell carcinoma in SCID/RAG2 mice. When lipid and drug levels were measured in established (>100-mg) tumors, accum ulation was more rapid in the LS180 tumors (C-max 4 h) than in the A431 tum ors (C-max 48 h). Mean area under the curve values for mitoxantrone measure d over a 96-h time course in A431 tumors were 505, 304, and 93 mu g . g(-1) . h(-1) for 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC)/cholesterol (Chol), 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC)/Chol, and free m itoxantrone, respectively. When a similar analysis was completed in LS180 t umors, the area under the curve values were 999, 749, and 251 mu g . g(-1) . h(-1) for DSPC/Chol, DMPC/Chol, and free mitoxantrone, respectively. Alth ough drug delivery was less after administration of the DMPC/Chol liposomal mitoxantrone compared with the DSPC/Chol formulation, LS180 solid-tumor gr owth curves showed the treatment with the DMPC/Chol formulation produced gr eater delays in tumor growth compared with animals treated with the DSPC/Ch ol formulation. These data emphasize the importance of designing liposomal formulations that release drug after localization within a region of tumor growth.