Nonaka Miki, Hirakata Mikito, Sakai Chizuka, Tomikawa Emi, Izawa Akiko, Nishi Tatsuya, Koga Yoko, Takahashi Kei, Shimozono Rieko, Ohshima Kaori, Narumi Hideki, Miyoshi Tomoya, Oshida Keiyu, Uchida Masashi, Uezono Yasuhito
Department of Pain Control Research, The Jikei University School of Medicine, 3-25-8, Nishi-Shimbashi, Minato-Ku, Tokyo, 105-8461, Japan.
Pharmaceutical Research Laboratories, Toray Industries, Inc, 6-10-1 Tebiro, Kamakura-City, Kanagawa, 248-8555, Japan.
Cardiovasc Toxicol. 2025 May 6. doi: 10.1007/s12012-025-09994-2.
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.
用于癌症化疗的蒽环类抗癌药物经常会引起心脏毒性，其发生率取决于累积剂量。TXB-001是一种新型的聚合物缀合吡柔比星（THP），与之前的P-THP（聚合THP）相比，具有更高的THP纯度和含量，预计其心脏毒性更低，对癌细胞的疗效更高。我们研究了TXB-001静脉给药后对心脏功能的影响及其药代动力学，并与小鼠体内现有的蒽环类药物（多柔比星（DOX）、多柔比星脂质体（DOXIL，DOX的脂质体制剂）、THP）进行了比较。超声心动图和心电图显示，DOX导致小鼠心脏功能障碍，并伴有器官重量、血液化学参数以及mRNA/蛋白质表达的变化。DOXIL和THP引起的变化与DOX相似，但程度较弱。在本研究条件下，TXB-001对心脏功能或相关变化没有显著影响。药代动力学评估结果显示，DOXIL和TXB-001从血浆到心脏组织的分布低于DOX和THP，而TXB-001的分布低于DOXIL。此外，与DOXIL不同，TXB-001没有表现出心脏蓄积。另外，TXB-001在心脏中的蒽环类药物暴露水平低于DOX、DOXIL和THP，暴露较少被认为是TXB-001在小鼠中低心脏毒性或无心脏毒性的一个原因。总体而言，这些结果表明TXB-001作为一种副作用比蒽环类药物少，尤其是心脏毒性小的抗癌药物的潜力。新型TXB-001可能成为一种心脏毒性较小的有效抗癌药物。
