Comparison of the therapeutic efficacy of 188Rhenium-liposomes and liposomal doxorubicin in a 4T1 murine orthotopic breast cancer model

Abstract

Liposomal doxorubicin (Lipo-DOX) has been widely and successfully used in chemotherapy for breast cancer patients. Since our previous studies found that 188Rhenium ( 188Re)-N,N-bis (2-mercaptoethyl)-N′, N′-diethy- lethylenediamine (BMEDA)-labeled pegylated liposomes ( 188Re-liposomes) have radiotherapeutic potential in a colon cancer model, and little information is available to make a comparison of the therapeutic efficacy of internal radiotherapy and chemotherapy, this study evaluates the therapeutic efficacy of 188Re-liposomes and Lipo-DOX, in a 4T1 murine orthotopic breast cancer model. MicroSPECT/CT imaging showed that the highest uptake of 188Re-liposomes was found at 24 h after intravenous administration. The results of a bio-distribution assay also demonstrated that the highest uptake of 188Re-liposomes in a tumor was 3.03 ± 0.29 (%ID/g) at 24 h, and that the highest tumor to muscle ratio was approximately 17 at 48 h. According to measurements of body weight and survival rate, the maximum tolerated doses (MTD) of 188Re-liposomes and Lipo-DOX were 37 MBq and 25 mg/kg, respectively. In a study of therapeutic efficacy, mice with 4T1 orthotopic breast tumors that were treated with 188Re-liposomes (4/5 MTD, 29.6 MBq) or Lipo-DOX (4/5 MTD, 20 mg/kg), showed a significant inhibition of tumor growth. In the small tumor model (50 mm 3), the lifespan of 4T1 tumor-bearing mice treated with 188Re-liposomes and Lipo-DOX was increased by 21.7 and 169.6%, respectively, compared to those treated with normal saline. In the large tumor model (300 mm 3), the lifespan of the 188Re-liposomes and the Lipo-DOX treated group was also increased by 35.2 and 141.2%, respectively. In this study, it was found that Lipo-DOX is better than 188Re- liposomes, for the treatment of 4T1 breast cancer. A further investigation of combined therapy, in a breast cancer model, using 188Re-liposomes and Lipo-Dox, to determine whether a synergistic effect exists, is ongoing in our laboratory.