Skorokhod Oleksli A, Garmaeva Tat'yana Ts, Vitvitsky Victor M, Isaev Valentin G, Parovichnikova Elena N, Savchenko Valerii G, Ataullakhanov Fazoil I
National Research Center for Hematology, Russian Academy of Medical Sciences, Moscow, Russia.
Med Sci Monit. 2004 Apr;10(4):PI55-64.
The objective of the present study was in vitro and in vivo investigation of erythrocytes as vehicles for anthracycline antibiotics.
MATERIAL/METHODS: The kinetics of daunorubicin binding with erythrocytes was studied in blood and in washed erythrocyte suspensions from healthy donors and patients with acute leukemia. The effect of daunorubicin on erythrocyte deformability was studied using cell filtration through membranes with 3 microm-diameter cylindrical pores. Erythrocyte-bound daunorubicin (EBD), prepared by equilibrating anticoagulated autologous blood with the antibiotic, was administered (45 or 60 mg/m2 body surface) to 14 leukemic patients as part of the 7+ 3 or RACOP courses. The pharmacokinetics of daunorubicin and its tolerability were studied.
Human erythrocytes bound daunorubicin (rubomycin) in citrated whole blood or in washed saline suspension. The equilibrium erythrocyte/medium daunorubicin concentration ratios (attained in 30-60 min at 37 degrees C) averaged 2.9 +/- 0.5 (n=13) in blood and 5.7 +/- 0.6 (n=8) in suspension (p<0.001), without any significant difference between the erythrocytes of donors and patients with acute drug-resistant leukemia or leukemic relapses. Incubation of patient blood with daunorubicin (0.5 mg/ml cells) did not affect erythrocyte deformability (filterability). After intravenous administration, the peak drug concentration and its elimination rate were lower for EBD than for free daunorubicin. The patients tolerated EBD better than its standard free form. In nine patients who received three EBD infusions, side effects were less frequent than in those treated with free daunorubicin.
Our results indicate that daunorubicin-loaded erythrocytes are promising for clinical application and deserve further clinical study.
本研究的目的是对作为蒽环类抗生素载体的红细胞进行体外和体内研究。
材料/方法：研究了柔红霉素与红细胞结合的动力学，对象为健康供体以及急性白血病患者的血液和洗涤后的红细胞悬液。使用通过直径为3微米的圆柱形孔膜进行细胞过滤的方法，研究了柔红霉素对红细胞变形性的影响。通过用抗生素平衡抗凝的自体血制备红细胞结合柔红霉素（EBD），将其以45或60mg/m²体表面积的剂量给予14例白血病患者，作为7+3或RACOP疗程的一部分。研究了柔红霉素的药代动力学及其耐受性。
人红细胞在枸橼酸化全血或洗涤后的盐水悬液中能结合柔红霉素（红比霉素）。红细胞/培养基中柔红霉素浓度的平衡比（在37℃下30-60分钟达到）在血液中平均为2.9±0.5（n=13），在悬液中为5.7±0.6（n=8）（p<0.001），供体红细胞与急性耐药白血病或白血病复发患者的红细胞之间无显著差异。用柔红霉素（0.5mg/ml细胞）孵育患者血液不会影响红细胞变形性（过滤性）。静脉给药后，EBD的药物峰值浓度及其消除率低于游离柔红霉素。患者对EBD的耐受性优于其标准游离形式。在接受三次EBD输注的9例患者中，副作用比接受游离柔红霉素治疗的患者更少。
我们的结果表明，负载柔红霉素的红细胞具有临床应用前景，值得进一步开展临床研究。
