Study Of Chronic Toxic Action Of EPI Polybutylcyanoacrylate Nanoparticles For Rats

Object: To study the tolerable dose and the maximal toxicity-free concentration range of EPI-PBCA-NP when repeated doses were given to normal rats for a long time period, and to observe the target organs of the toxic action, the reversibility of tissue morphology and functions after withdrawal of EPI-PBCA-NP, so as to provide a theoretical basis for its clinical application.Methods: A total of 150 SD rats(75 female, 75 male), were evenly randomized into 5 groups, every group including 30 rats. group 1: normal control(normal saline); group 2: blank nanoparticles group (PBCA-NP, 115.10mg/kg);group 3: lower concentration EPI-PBCA-NP (26.81mg/kg); group 4: medium concentration EPI-PBCA-NP (61.59mg/kg), and group 5: high concentration EPI-PBCA-NP group (141.49mg/kg). Tail vein injection, once every 3 weeks for 3 months. Two thirds of the animals were sacrificed at specified time points and the specimens were harvested; another one third of the animals were spared for another 2 weeks to observe the reversibility of morphology and functions after withdrawal of the drug. The examination items included: the general condition, the toxic action, hematological parameters, blood biochemistry parameters, system anatomy, pathohistological examination and organ coefficient. All the data were analyzed with SPSS11.5 software.Results: In the chronic toxic trial of EPI-PBCA-NP, it was found that the behaviors and pathohistological examination of rats in group 2 and group 3 were normal, the hematological parameters, blood biochemistry parameters, weighing and organ coefficient parameters had no significant difference with those of group 1 (P＞0.05). In group 4, rats shows slightly toxic action; weighing increased step down; organ coefficient parameters and their pathohistological examination shows different degree pathological lesions in liver and heart; hematological parameters and blood biochemistry parameters analysis found that ALT,AST,CK,CKMB and LDH were all increased, but PLT,WBC,TP,ALB,GLO decreased compared with those of group 1 (P＜0.05), which was reversible after withdrawal of the drug. The toxic reaction in group 5 was even more obvious (partially irreversible), with significant difference also found between group 5 and group 4 (P＜0.05).Conclusion: EPI-PBCA-NP has less toxicity to the heart and marrow compared with EPI for excellent stable liver target effect, it was determined that the maximal toxicity-free concentration range is 26.81mg/kg(EPI: 5.0mg/kg), the dose is higher than that EPI treatment dose, showing promise for theⅢphase clinical trial.