The Pharmacokinetics And Tumor Targeting Evaluation Of HCPT Nanosuspensions

Hydroxycamptothecin(HCPT) is an enzyme topoisomerase I inhibitor, which can inhibit the synthesis of DNA and leads to the death of tumor cells. HCPT has been shown to have a strong antitumor activity against hepatoma, gastric carcinoma, lung cancer, cystic carcinoma, tumor of head and neck, leukemia and so on.HCPT nanosuspensions were prepared by the precipitation combined high pressure homogenization technique. The pharmacokinetics, biodistribution and tumor targeting were studied. In the present work we can provide some academic and experimental data for the further research of HCPT nanosuspension.The preparation methods, formulation and preparation process were studied. HCPT nanosuspensions obtained from the precipitation methos, the high pressure homogenization method, the precipitation combined high pressure homogenization method, and the influence of the stabilizers, the homogenization pressure and cycles were also studied. The formulations and the preparation process were optimized in this experiment. The droplet size, PDI and Zeta potential of HCPT nanosuspensions were (281.6±10.0)nm, (0.166±0.028) and (-33.98±0.90)mV, resectively.The method of high performance liquid chromatography was set up to determine the concentration of HCPT in rat plasma, which can provide the academic base for the pharmacokinetics of HCPT. After 4. 0mg·kg-1 tail intravenous injection, using camptothecin (CPT) as internal standard, the plasma were extracted by ethyl acetate and chromatographed on a DiamonsilTM C18 column with a mobile phase consisting of acetonitrile-0.1% triethylamine buffer solution(PH=3)(25:75, v/v). The detection wavelength is at 384 nm. The determined HCPT concentrations were calculated by 3P97 pharmacokinetic program. The results showed that the standard curves of HCPT in rat plasma were Y=0.024C+0.1686, R=0.9997, linear range:1-50 ng·mL-1, and Y=0.0236C+0.5951, R=0.9999, linear range:50-5000ng·mL-1,respectively. The lowest limit of quantification in plasma was 1 ng·mL-1. The precision and recovery of HCPT in rat plasma could satisfy the technical requirements of the analysis of biological samples. The t1/2(a) of HCPT nanosuspension and HCPT injection were (0.19±0.03)h and (0.09±0.03)h, t1/2(β) were (3.40±0.64)h and (0.57±0.14)h, MRT were (4.67±0.74)h and (0.82±0.20)h, AUC were (1467.29±170.27) h·ng·mL-1 and (621.19±180.95)h·ng·mL-1, respectively. Consequently, HCPT nanosuspensions can significantly prolong half-life of HCPT, and improve the bioavailability.The method of high performance liquid chromatography(HPLC) was set up to determine the concentration of HCPT in different tissues. The retention time of HCPT and CPT were 10.5min and 23.0min, respectively. The linear relations of HCPT in different tissues were good, the precision and recovery of HCPT in low, middle, high concentrations could satisfy the technical requirements of the analysis of biological samples. The lowest limit of quantification of HCPT in tissues was 25 ng·mL-1. The results showed that the AUC of HCPT nanosuspension in tumor is 3.5 times higher than that of HCPT injection. HCPT nanosuspension has a tissue targeting in heart, lung, kidney, stomach,small intestine and blood.