Cardiac toxicity of doxorubicin loaded PEG_2K-(Fmoc)lys-NLG₉₁₉micelle: in vitro and in vivo evaluation experiment

Objective To explore the cardiac toxicity of doxorubicin loaded PEG_2K-(Fmoc)lys-NLG₉₁₉'s micelle and drug free micelle in vitro and in vivo. Methods For in vitro study, newborn rat's mycardial cells are treated with a seriers concentrations of free doxorubicin, free carrier and doxorubicin loaded micelle, and the differences of cell viabilities were evaluated by MTT assay. For in vivo study, 20 mice are randomly divided into four groups:control group (n=5), free DOX group(n=5), free carrier group (n=5), DOX loaded micelle group (n=5). Mice in four groups are treated by 3 times injection of Saline, free doxorubicin, free carrier and doxorubicin loaded micelle, respectively. After last injection, serum were tested for the level of CK, CK-MB and LDH. All the mice were sacrifced and their hearts were examined by H& E staining to observe the changes of mycardial cells by microscope. Results For in vitro study, drug free micelle with different concentrations have no cardiac toxicity (P> 0.05). The cell viability of the DOX loaded micelles group(DOX 1ng/ml) was signifcantly higher than that of free DOX group(DOX 1 ng/ml) (74.48%±6.16% vs 53.12%±6.84%,P< 0.05). For in vivo study, serum levels of CK, CK-MB, LDH in free carrier group((333.73±51.60)U/L, (43.07±2.17) U/L, (657.33±23.94) U/L)and in DOX loaded micelle groupCK (538.27±48.71)U/L, CK-MB (53.60±2.10)U/L, LDH (857.33±16.46) U/L) were signifcantly lower than those in free DOX group (CK (1 307.67±81.64)U/L; CK-MB (151.07±12.33) U/L; LDH (2610.67±21.39)U/L. P< 0.05, respectively).The pathological changes in HE staining showed the DOX induced myocardial damage seriously, but no obvious myocardial damage was observed in the free carrier and DOX loaded micelle group. Conclusion The drug free PEG_2K-(Fmoc) lys-NLG₉₁₉carrier have no cardiac toxicity. Doxorubicin loaded PEG_2K-(Fmoc) lys-NLG₉₁₉micelle can obviously reduce the cardiac toxicity from doxorubicin.