Chemoradionuclide Therapy with 186Re-Labeled Liposomal Doxorubicin: Toxicity, Dosimetry, and Therapeutic Response

This study was performed to determine the maximum tolerated dose (MTD) and therapeutic effects of rhenium-186 (Re-186)-labeled liposomal doxorubicin (Doxil), investigate associated toxicities, and calculate radiation absorbed dose in head and neck tumor xenografts and normal organs. Doxil and control polyethylene glycol (PEG)-liposomes were labeled using Re-186-N,N-bis(2-mercaptoethyl)-N',N'-diethylethylenediamine (BMEDA) method. Tumor-bearing rats received either no therapy (n = 6), intravenous Doxil (n = 4), or escalating radioactivity of Re-186-Doxil (185-925 MBq/kg) or Re-186-PEG-liposomes (1110-1665 MBq/kg) and were monitored for 28 days. Based on body weight loss and systemic toxicity, MTD for Re-186-Doxil and Re-186-PEG-liposomes were established at injected radioactivity/body weight of 740 and 1480 MBq/kg, respectively. Re-186-injected radioactivity/body weight for therapy studies was determined to be 555 MBq/kg for Re-186-Doxil and 1295 MBq/kg for Re-186-PEG-liposomes. All groups recovered from their body weight loss, leucopenia, and thrombocytopenia by 28 days postinjection. Normalized radiation absorbed dose to tumor was significantly higher for Re-186-Doxil (0.299 +/- 0.109 Gy/MBq) compared with Re-186-PEG-liposomes (0.096 +/- 0.120 Gy/MBq) (p < 0.05). In a separate therapy study, tumor volumes were significantly smaller for Re-186-Doxil (555 MBq/kg) compared with Re-186-PEG-liposomes (1295 MBq/kg) (p < 0.01) at 42 days postinjection. In conclusion, combination chemoradionuclide therapy with Re-186-Doxil has promising potential, because good tumor control was achieved with limited associated toxicity.