Acute toxicity study of cisplatin loaded long-circulating and pH-sensitive liposomes administered in mice.

Cisplatin (CDDP) is a very active and cytotoxic agent but causes severe side effects, namely nephrotoxicity, which limits the therapy. The present study aimed to evaluate the acute toxicity of long-circulating and pH-sensitive liposomes containing cisplatin (SpHL-CDDP), as compared to free CDDP, after their intravenous administration in mice. After the administration of free CDDP or SpHL-CDDP at different doses, the body weight was recorded and the LD50 and the maximum tolerated dose (MTD) were calculated. Blood samples were collected for hematological and biochemical analysis. Kidneys, liver, spleen, and bone marrow were removed for histopathological examination. A reduction of body weight of less than 15% could be observed in male and female mice after treatment with free CDDP and SpHL-CDDP at doses of < or = 10 mg/kg and 20 mg/kg, respectively. The LD50 and MTD values obtained after SpHL-CDDP administration were approximately two and three times higher, respectively, than those obtained using free CDDP. Changes in hematological parameters and hematopoietic tissue morphology showed the appearance of toxicity induced by free CDDP. By contrast, the absence of mielotoxicity after SpHL-CDDP treatment could be observed. As regards nephrotoxicity, no alteration in blood urea and creatinine levels, nor morphological change in kidneys, could be observed in mice treated with SpHL-CDDP, as compared to saline-treatment control group. The results showed that SpHL-CDDP at its MTD (20 mg/kg), as compared to the administration of free CDDP at its MTD (7.5 mg/kg), significantly reduced the renal toxicity. Thus, SpHL-CDDP can eliminate CDDP-induced toxicity and is a promising candidate for the intravenous therapy of solid tumors.