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

Abstract

This study was performed to determine the maximum tolerated dose (MTD) and therapeutic effects of rhenium-186 (¹⁸⁶Re)-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 ¹⁸⁶Re-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 ¹⁸⁶Re-Doxil (185–925 MBq/kg) or ¹⁸⁶Re-PEG-liposomes (1110–1665 MBq/kg) and were monitored for 28 days. Based on body weight loss and systemic toxicity, MTD for ¹⁸⁶Re-Doxil and ¹⁸⁶Re-PEG-liposomes were established at injected radioactivity/body weight of 740 and 1480 MBq/kg, respectively. ¹⁸⁶Re-injected radioactivity/body weight for therapy studies was determined to be 555 MBq/kg for ¹⁸⁶Re-Doxil and 1295 MBq/kg for ¹⁸⁶Re-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 ¹⁸⁶Re-Doxil (0.299±0.109 Gy/MBq) compared with ¹⁸⁶Re-PEG-liposomes (0.096±0.120 Gy/MBq) (p<0.05). In a separate therapy study, tumor volumes were significantly smaller for ¹⁸⁶Re-Doxil (555 MBq/kg) compared with ¹⁸⁶Re-PEG-liposomes (1295 MBq/kg) (p<0.01) at 42 days postinjection. In conclusion, combination chemoradionuclide therapy with ¹⁸⁶Re-Doxil has promising potential, because good tumor control was achieved with limited associated toxicity.