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

Abstract

Abstract. Liposomal doxorubicin (Lipo-DOX) has been widely and successfully used in chemotherapy for breast cancer patients. Since our previous studies found that 188 Rhenium ( 188 Re)-N,N-bis (2-mercaptoethyl)-N',N'-diethylethylenediamine (BMEDA)-labeled pegylated liposomes ( 188 Re-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 188 Re-liposomes and Lipo-DOX, in a 4T1 murine orthotopic breast cancer model. MicroSPECT/CT imaging showed that the highest uptake of 188 Re-liposomes was found at 24 h after intravenous administration. The results of a biodistribution assay also demonstrated that the highest uptake of 188 Re-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 188 Re-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 188 Re-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 188 Re-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 188 Re-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 188 Re-liposomes, for the treatment of 4T1 breast cancer. A further investigation of combined therapy, in a breast cancer model, using 188 Re-liposomes and Lipo-Dox, to determine whether a synergistic effect exists, is ongoing in our laboratory.

DAFODIL: A novel liposome-encapsulated synergistic combination of doxorubicin and 5FU for low dose chemotherapy

“…Mice were treated with 4 total injections of 3 mg/kg DOX and 0.62 mg/kg 5FURW, for a total DOX and 5FURW dose of 12 mg/kg and 2.5 mg/kg, respectively. To the best of our knowledge, never before has cumulative DOX doses <15 mg/kg been able to inhibit aggressive 4T1 tumor growth by >90%, regardless of its use as a single agent or in combination with another chemotherapy drug [44, 65–72]. Doxil alone is required at doses of 20 mg/kg to provide significant 4T1 tumor reduction, as reported by previous studies [44].…”

“…5b). To the best of our knowledge, this is the first time that 4T1 tumor growth was inhibited by >90% at a cumulative DOX dose <15 mg/kg, either used as a single agent or combined with another chemotherapy drug [44, 65–72]. Biodistribution studies were conducted to see if antitumor efficacy was dictated by high uptake in tumors (Fig.…”

“…Liposomes exhibited biodistributions and clearance (Fig. S9a) typical of PEGylated liposomes [43, 44, 73], with greatest accumulation occurring in the liver and spleen, and 2.3% initial dose per g (ID/g) present in tumors. Therefore, the enhanced antitumor efficacy is likely attributed to the potent synergistic interactions between 5FURW and DOX and not enhanced tumor accumulation.…”

“…To the best of our knowledge, never before has cumulative DOX doses <15 mg/kg been able to inhibit aggressive 4T1 tumor growth by >90%, regardless of its use as a single agent or in combination with another chemotherapy drug [44, 65–72]. Doxil alone is required at doses of 20 mg/kg to provide significant 4T1 tumor reduction, as reported by previous studies [44]. This is also the first instance of 5FU-liposomes which were both well-tolerated and effective at inhibiting tumor growth, let alone at remarkably low doses [55, 85].…”

“…Here we report such synergistic combination and a method of encapsulating it in a liposome to deliver it to tumors. Since liposomes and nanoparticles in general exhibit low tumor accumulation, about 1.5–2.0% initial dose per g of tumor tissue [42–44], it is essential that the combination is co-delivered in a single vehicle. The liposomal co-encapsulation of 5FU and DOX ensures that the optimally identified synergistic ratio is exposed to the tumor cells, thereby achieving the most therapeutic benefit from the combination.…”