TXB-001, A Newly-Developed Polymer-Conjugated Anthracycline, Alleviates Anthracycline-Induced Cardiotoxicity.

Abstract

Anthracycline anti-cancer drugs, which are used in cancer chemotherapy, frequently cause cardiotoxicity, the incidence of which depends on cumulative doses. TXB-001 is a new candidate polymer-conjugated pirarubicin (THP) with higher THP purity and content compared to previous P-THP (polymerized THP) and is expected to exhibit lower cardiotoxicity and higher efficacy against cancer cells. We examined the effects of TXB-001 on cardiac function and the pharmacokinetics after its intravenous administration compared with those of existing anthracyclines (doxorubicin (DOX), DOXIL (liposomal formulation of DOX), THP) in mice. Echocardiography and electrocardiography showed that DOX caused cardiac dysfunction in mice, with associated changes in organ weights, blood chemical parameters, and mRNA/protein expressions. DOXIL and THP induced similar, but weaker changes than DOX. TXB-001 did not significantly affect cardiac function or associated changes under the conditions of this study. The results of the pharmacokinetic evaluation revealed that the distributions of DOXIL and TXB-001 from plasma to heart tissue were lower than those of DOX and THP, while the distribution of TXB-001 was lower than that of DOXIL. Furthermore, TXB-001 did not show cardiac accumulation in contrast to DOXIL. In addition, the anthracycline exposure level of TXB-001 in the heart was lower than those of DOX, DOXIL, and THP, with less exposure being regarded as one reason for the low or no cardiotoxicity of TXB-001 in mice. Collectively, these results suggest the potential of TXB-001 as an anti-cancer drug with fewer side effects than anthracyclines, particularly cardiotoxicity. Novel TXB-001 may become an effective anti-cancer drug with fewer cardiotoxicity.