P167肽修饰的多柔比星长循环脂质体在大鼠体内的药动学和药效学

In vivo study on pharmacokinetics and pharmacodynamics of P167 modified liposomal doxorubicin in rats

目的研究P167肽修饰对多柔比星脂质体大鼠静脉给药的体内药动学和药效学的影响。方法通过pH梯度法分别制备多柔比星长循环脂质体(DOX-SSL)和P167肽修饰的多柔比星长循环脂质体(DOX-P167-SSL)。12只SD大鼠随机分为2组,分别尾静脉注射DOX-SSL和DOX-P167-SSL,给药剂量为2.5 mg·kg-1。采用HPLC内标法测定不同给药时间的血清多柔比星浓度,用WinNonlin软件拟合并计算药动学参数。制备大鼠脑胶质瘤模型,经核磁扫描测定肿瘤体积,均匀分组,分别尾静脉注射生理盐水、DOX-SSL和DOX-P167-SSL,每组6只动物,给药剂量为2.5 mg·kg-1,3 d给药1次,共给药5次。以相对肿瘤增殖率(T/C%)为指标评价药效。结果 DOX-SSL和DOX-P167-SSL大鼠尾静脉给药后,均符合二室模型。DOXP167-SSL组的t1/2(α)、t1/2(β)及AUC分别为4.89 min、837.57 min、610.35 min·mg·L-1,均低于DOX-SSL组的16.23、2 940.48和1 301.16 min·mg·L-1。DOX-P167-SSL组T/C%为7.32%,而DOX-SSL组为37.07%。结论 P167肽的修饰使多柔比星长循环脂质体的长循环效果降低,但药效得到明显提高,这可能与P167肽的穿透作用有关。

AIM To study the effect of P167 peptide modification on the pharmacokinetics and pharmacodynanlics of doxorubicin-loaded liposomes（DOX-SSL）. METHODS DOX-SSL and P167 peptide modified doxorubicin-loaded li- posomes （DOX-P167-SSL） were prepared using pH gradient method. Sprague dawley rats were randomly divided into 2 groups （six rats per group） and treated with DOX-SSL, DOX-P167-SSL via tail vein at a dose of 2.5 mg kg-1 respec- tively. HPLC internal standard method （daunomycin as internal standard substance） was used to determine the concentra- tion of doxorubicin in blood serum. WinNonlin software was used to calculate pharmacokinetic parameters. Tumor-bearing rats （C6 glioma） were established and the rats were divided into 3 groups according to the results of magnetic resonance imaging （MRI）. Rats were administered with physiological saline, DOX-SSL and DOX-P167-SSL via tail vein at a dose of 2.5 rag＂ kg- t, respectively. Administration was made once every 3 days with total 5 doses per rat. Relative tumor growth ratio （T/C%） was calculated to evaluate the efficacy of drug. RESULTS After tail vein administration, the biodistribution of two formulations fitted into two-compartment model. The tl/2（a） , t1/2（β） and AUC of DOX-PI67-SSL were 4.89 rain, 837.57 rain and 610.35 rain＂ mg＂ L- 1 respectively, lower than that of DOX-SSL （ 16.23 min, 2 940.48 min and 1 301.16 min mg L- 1 ）. The T/C % treated by DOX-P167-SSL was 7.32 %, while 37.07 % for DOX-SSL. CONCLUSION The modification of P167 peptide leads to a decline in long circulation of DOX-SSL, but an obvious increase in efficacy, it may be a result of the penetration of P167 peptide.