STUDIES ON THE MYELOSUPPRESSIVE ACTIVITY OF DOXORUBICIN ENTRAPPED IN LIPOSOMES
STUDIES ON THE MYELOSUPPRESSIVE ACTIVITY OF DOXORUBICIN ENTRAPPED IN LIPOSOMES
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DOI：
10.1007/bf00689270
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发表时间：
1990-01-01
影响因子：
3
通讯作者：
MAYER, LD
中科院分区：
文献类型：
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作者：
BALLY, MB;NAYAR, R;MAYER, LD
在小鼠中，通过测量脾重量、外周白色血细胞（WBC）和骨髓有核细胞的变化来定量包封在不同脂质组成和大小的脂质体中的阿霉素的骨髓抑制活性。在以20 mg/kg的剂量i. v.给予游离多柔比星后，在第3天观察到骨髓细胞减少90%。到第7天，骨髓有核细胞计数与对照值相似。施用包封在大（直径约1.0 μ m）卵磷脂酰胆碱/胆固醇（EPC/Chol）（摩尔比，55：45）脂质体中的等效剂量的阿霉素诱导骨髓细胞构成减少80%，持续>7天的时间。在施用用二硬脂酰磷脂酰胆碱/胆固醇（DSPC/Chol）（摩尔比55：45）配制的大（1.0 μ m）脂质体多柔比星系统后获得了类似的结果。相比之下，使用小（直径，约0.5 μ m）的多柔比星制备脂质体。0.1μ m）DSPC/Chol脂质体仅诱导骨髓细胞构成减少40%（第3天），其在第7天恢复到对照值。多柔比星介导的骨髓抑制活性的其他指标（脾脏重量减轻和外周血白细胞减少）与骨髓细胞结构的变化密切相关。然而，在用小（0.1-μ m）DSPC/Chol脂质体多柔比星治疗的动物中观察到一个例外，其显示外周白细胞减少症持续> 14天。在施用小（0.1-μ m）EPC/Chol脂质体阿霉素后没有观察到这种延长的白细胞减少。定量骨髓相关脂质体脂质和多柔比星，以确定多柔比星介导的骨髓毒性的程度是否与包埋药物的生物分布变化相关。已经证明，当药物被封装在大脂质体中时，比当药物与小脂质体结合时，多10-20倍的多柔比星被递送到骨髓。这些数据是有用的，在定义脂质体制剂的特点，调节骨髓抑制行为的包埋药物。
The myelosuppressive activity of doxorubicin encapsulated in liposomes of differing lipid composition and size was quantified in mice by measurement of changes in spleen weight, peripheral white blood cells (WBC), and bone marrow nucleated cells. Following i.v. administration of free doxorubicin at a dose of 20 mg/kg, a 90% reduction in marrow cellularity was observed on day 3. The marrow nucleated cell count was similar to control values by day 7. Administration of an equivalent dose of doxorubicin that was encapsulated in large (diameter .apprx.1.0 .mu.m) egg phosphatidylcholine/cholesterol (EPC/Chol)(molar ratio, 55:45) liposomes induced an 80% reduction in bone marrow cellularity that lasted for periods of >7 days. Similar results were obtained following administration of large (1.0 .mu.m) liposomal doxorubicin systems formulated with distearoylphosphatidylcholine/cholesterol (DSPC/Chol) (molar ratio 55:45). In contrast, liposomal doxorubicin prepared using small (diameter, .apprx. 0.1 .mu.m) DSPC/Chol liposomes induced only a 40% reduction (day 3) in bone marrow cellularity, which returned to control values by day 7. Other indicators of doxorubincin-mediated myelosuppressive activity (spleen weight loss and peripheral leukopenia) correlated well with changes observed in marrow cellularity. An exception to this, however, was observed in animals treated with small (0.1-.mu.m) DSPC/Chol liposomal doxorubicin, which displayed peripheral leukopenia for periods of > 14 days. This extended leukopenia was not observed following administration of small (0.1-.mu.m) EPC/Chol liposomal doxorubicin. Marrow-associated liposomal lipid and doxorubicin were quantified to determine if the extend of doxorubicin-mediated myeloid toxicity could be correlated to changes in biodistribution of the entrapped drug. It was demonstrated that 10-20 times more doxorubicin is delivered to the bone marrow when the drug is given encapsulated in large liposomes than when it is associated with small liposomes. These data are useful in defining characteristics of liposomal preparations that modulate the myelosuppressive behaviour of entrapped antineoplastic agents.