Doxorubicin-induced chronic cardiotoxicity and its protection by liposomal administration.

ABSTRACT

The chronic cardiotoxicity of doxorubicin as a free drug or entrapped in positive and negative liposomes was morphologically evaluated in mice treated seven times i.v. at a dose of 4 mg/kg. Liposomes were composed of phosphatidylcholine, cholesterol, and stearylamine (positive charge) or phosphatidylserine (negative charge). Administration of free doxorubicin caused a pattern of cardiac damage characterized by loss of myofiber elements, mitochondrial damage, nuclear abnormalities, swollen and distended sarcoplasmic reticulum leading to vacuolization, and increasing myeloid body accumulation. Cardiac tissues of mice treated with doxorubicin entrapped in negatively charged liposomes demonstrated pronounced loss of filaments, enlarged mitochondria, disruptive loss of crests, and expanded nuclear membrane. However, electron microscopic examination of the cardiac muscles of mice treated with positive liposomes demonstrated a significant protection from drug-induced toxicity, with only minor loss of parallel fibrillar arrangement and myofilaments in limited focal areas. The majority of the tissue demonstrated normal vasculature and intercalation of myocytes as compared to control groups. The mean qualitative and quantitative scores of toxic lesions for free doxorubicin and entrapped in negative liposomes are 2.7 and 2.23, respectively. However, the mean score for the group of mice treated with positive liposomes is only 1.12, showing a better than 2-fold scoring protection of both the extent and severity of cardiac lesions.