论文部分内容阅读
Objective: We prepared the norcantharidin loaded into poly (MePEGcyanoacrylate-co-hexadecylcyanoacrylate) nanoparticles, determined the characteristics and in vitro release of NCTD from the nanoparticles and investigated the pharmacokinetics and tissue distribution of the drug after administering low, medium and high dosages of NCTD solution and NCTD/PEGs000-PHDCA NPs in beagle dogs and SD rats, respectively.These studies revealed the variation in the pharmacokinetic parameters.Methods: The NCTD-loaded NPs were preparaed using a modified spontaneous emulsification solvent diffusion method (modified-SESD).The in vitro drug release behaviour of the NCTD/PEG-PHDCA NPs was investigated in phosphate buffered saline (PBS, pH 6.8) using a dialysis-diffusion method.NCTD of pharrnacokinetics in beagle dogs and tissue distribution in SD rats were studied.Results: The shape of NCTD/PEG-PHDCA NPs were spherical.The mean particle size, PDI, Zeta potential were (140.80 ± 2.49) nm, (0.23 ± 0.02) , (-8.16 ± 0.12) mV, The Weibull equation better described the process (r =0.9337), therefore the equation of ln ln [1/(1-Q)] =1.8147 lnt-1.9582 can be used to describe the release profile for NCTD/PEG-PHDCA NPs.Across the investigated dosage range, NCTD demonstrated dose-dependent kinetics with enhanced T1/2 α, T1/2 β and AUC0-12 and an apparently shrinking Vd with increasing dosage.However, the NCTD solution and nanoparticle groups both demonstrated nonlinear, dose-dependent kinetics with enhanced AUC0-24 with increasing dosage.Tissue distribution study in SD rats demenonstrated that after three doses administrated, NCTD/MePEGs000-PHDCA NPs would enhance the NCTD concentration in liver, while the risk of higher toxicity in kidney was increased.Conclusion: The NCTD-loaded NPs was preparaed successfully.The pharmacokinetic study demonstrated nonlinear, dose-dependent kinetics, suggesting that the risk of NCTD intoxication may increase nonproportionally at higher doses.The tissue distribution results showed that NCTD/MePEGs000-PHDCA NPs would enhance the NCTD concentration in liver, in the meanwhile, the risk of higher toxicity in kidney was increased.