Preclinical evaluation of early multi-organ toxicity induced by liposomal doxorubicin using ⁶⁷Ga-citrate

Abstract

Although liposomal doxorubicin (LPD) is widely used for cancer treatment, knowledge concerning the toxicity induced by this drug in healthy organs and tissues is limited. LPD-induced toxicity studies relative to free doxorubicin (DOX) have focused on cardiotoxicity in tumor-bearing animals. On the other hand, the results on DOX-induced cardiotoxicity depending on gender are controversial. One of the manifestations of toxicity is tissue inflammation. ⁶⁷Ga-citrate has been used for decades to assess inflammation in various pathologies. In this work, the ex vivo biodistribution of ⁶⁷Ga-citrate is used to evaluate induced multi-organ toxicity in healthy 10-week-old male and female CD1 mice treated for 5 weeks with LPD. Toxicity in males, determined by ⁶⁷Ga-citrate, was evident only in the target organs of liposomes (spleen, liver, kidneys, and lungs); the average weight loss was 11% and mortality was 14%. In female mice, ⁶⁷Ga-citrate revealed a cytotoxic effect in practically all organs, the average weight loss was 37%, and the mortality after the last dose of LPD was 66%. These results confirm the usefulness of ⁶⁷Ga-citrate and the importance of stratifying by sex in the toxicological evaluation of drugs.

Keywords:

• Liposomal doxorubicin
• ⁶⁷Ga-citrate
• multi-organ toxicity
• biodistribution

Acknowledgments

This work was carried out as a part of the activities of the ‘Laboratorio Nacional de Investigación y Desarrollo de Radiofármacos’ (LANIDER-CONACyT, Mexico) and the research network ‘Investigación en Farmacia y Teranóstica’ (UAEMex, Mexico). Finally, the critiques and comments on this work and the scientific discussions with Dr. Eunice Olivé-Álvarez are also acknowledged.

Disclosure statement

The authors declare no conflicts of interest.

Additional information

Funding

The authors acknowledge the financial support received from the State of Mexico-Council for Science and Technology/Consejo Mexiquense de Ciencia y Tecnología (COMECyT, Mexico), through the grant FICDTEM-2021-021.