Antitumor efficacy and reduced systemic toxicity of palmitic acid-modified pirarubicin nanoparticles in mice

Pirarubicin (THP) is a potent anthracycline anticancer agent; however, its clinical use is limited by nonselective tissue distribution and systemic toxicity. This study aimed to evaluate whether palmitic acid-modified THP nanoparticles (Pal-THP nanoparticles) could improve the in vivo therapeutic profile of THP.

Pal-THP nanoparticles stabilized by albumin as a formulation stabilizer were prepared by antisolvent precipitation. Antitumor efficacy, biodistribution, and drug forms (intact Pal-THP and the free THP released from Pal-THP) were evaluated in colon 26 tumor-bearing mice following intravenous administration. Acute systemic and hemolytic toxicity were assessed relative to THP.

Pal-THP nanoparticles significantly suppressed tumor growth compared with the control group, without inducing body weight loss, whereas THP exhibited a tendency toward tumor suppression but did not reach statistical significance versus control at an equivalent dose. While the absolute tumor accumulation of Pal-THP nanoparticles was limited, it was significantly higher than that of THP. Importantly, there was efficient conversion of Pal-THP to free THP in tumor tissue, which is consistent with the presence of an acid‑labile hydrazone linkage. Pal-THP nanoparticles also markedly attenuated acute systemic and hemolytic toxicity, in contrast to THP, under the present experimental conditions.

Pal-THP nanoparticles altered the in vivo fate of THP through tumor accumulation and tumor-localized conversion to free THP. This resulted in effective tumor suppression and a significant reduction in toxicity compared to THP in mice. Thus, this formulation strategy represents a promising approach for improving the therapeutic index of chemotherapy using THP and other anthracyclines.