Improved in vivo Antitumor Efficacy and Reduced Systemic Toxicity of Carboxymethylpullulan‐peptide‐doxorubicin Conjugates

The antitumor efficacy of the conjugate of doxorubicin (DXR) and carboxymethylpullulan (CMPul) with Phe‐Gly spacer (CMPul‐FG‐DXR) was evaluated using murine tumor models and compared with that of DXR. The conjugate exhibited higher antitumor efficacy against Lewis lung carcinoma than DXR. Complete tumor regression followed by long‐term tumor‐free survival was frequently observed when CMPul‐FG‐DXR was administered i.v. three times at a dose equivalent to 10 mg/kg of DXR. The superior survival as well as anti‐metastatic effect of CMPul‐FG‐DXR in comparison with DXR was also demonstrated with the M5076 murine reticulosarcoma model. Body weight loss in mice treated with the conjugate was less than that in the DXR‐treated group, indicating lower systemic toxicity of CMPul‐FG‐DXR. Simply mixing CMPul with DXR did not enhance the antitumor activity of DXR, showing that the conjugation of DXR with CMPul is necessary for improved antitumor activity. However, no enhanced antitumor efficacy of the conjugates was observed against a non‐solid tumor model such as P388 leukemia. In summary, improved antitumor efficacy with reduced systemic toxicity of CMPul‐FG‐DXR was demonstrated in the present study. CMPul‐FG‐DXR may be useful as a cancer chemotherapy agent against solid tumors and metastases.