Reszka R, Beck P, Fichtner I, Hentschel M, Richter J, Kreuter J
Max-Delbrück Center for Molecular Medicine, Berlin, Germany.
J Pharmacol Exp Ther. 1997 Jan;280(1):232-7.
B16-melanoma-bearing mice were treated with four different formulations containing equivalent doses of the highly effective antineoplastic drug mitoxantrone. The formulations were: A mitoxantrone solution, a negatively charged liposome preparation (small unilamellar vesicles), a 14C-labeled polybutylcyanoacrylate- (PBCA) nanoparticle suspension, and a suspension of poloxamine 1508-coated 14C-PBCA-nanoparticles. After 1, 4 and 24 hr, three animals of each group were killed and the mitoxantrone concentrations in the blood, tumor, liver, spleen, heart and bone marrow were determined using an high performance liquid chromatography technique. Additionally, the concentrations of PBCA particles in the same tissues were measured by scintillation counting to compare the mitoxantrone distribution with the corresponding PBCA nanoparticle distribution. Each formulation led to a different body distribution profile of the drug. Liposomes drastically increased the blood level of mitoxantrone even after 24 hr, although free drug was cleared quickly. Liposomes also raised the concentration in the liver and spleen, but not the drug level in the tumor. PBCA-nanoparticles considerably increased the mitoxantrone concentrations in tumor, heart and spleen. However, the increase in tumor concentrations was not statistically significant due to the high variability. Nevertheless, the tumor growth was reduced significantly (P < .05) compared to both, the liposome and the solution preparation. The nanoparticle polymer concentrations did not completely mirror those of the drug concentrations. Especially in the heart, where no nanoparticle polymer radioactivity was found, the particle concentration did not completely correspond to the mitoxantrone concentration, revealing that a part of the drug was lost from the particles. These pharmacokinetic results correspond to parallel therapeutic effects obtained with mitoxantrone-loaded nanoparticles and liposomes in the B16 melanoma.
用含有等量高效抗肿瘤药物米托蒽醌的四种不同制剂对荷B16黑色素瘤的小鼠进行治疗。这些制剂分别是：米托蒽醌溶液、带负电荷的脂质体制剂（小单层囊泡）、14C标记的聚氰基丙烯酸正丁酯（PBCA）纳米颗粒悬液以及泊洛沙明1508包被的14C-PBCA纳米颗粒悬液。在1小时、4小时和24小时后，每组处死三只动物，采用高效液相色谱技术测定血液、肿瘤、肝脏、脾脏、心脏和骨髓中的米托蒽醌浓度。此外，通过闪烁计数测量相同组织中PBCA颗粒的浓度，以比较米托蒽醌分布与相应PBCA纳米颗粒分布。每种制剂导致药物在体内的分布情况不同。脂质体即使在24小时后仍能显著提高米托蒽醌的血药浓度，尽管游离药物清除迅速。脂质体还提高了肝脏和脾脏中的浓度，但未提高肿瘤中的药物水平。PBCA纳米颗粒显著提高了肿瘤、心脏和脾脏中的米托蒽醌浓度。然而，由于变异性高，肿瘤浓度的增加无统计学意义。尽管如此，与脂质体和溶液制剂相比，肿瘤生长显著降低（P < 0.05）。纳米颗粒聚合物浓度并未完全反映药物浓度。特别是在心脏中，未发现纳米颗粒聚合物放射性，颗粒浓度与米托蒽醌浓度不完全对应，表明部分药物从颗粒中流失。这些药代动力学结果与用载有米托蒽醌的纳米颗粒和脂质体在B16黑色素瘤中获得的平行治疗效果相符。
