Zocchi E, Tonetti M, Polvani C, Guida L, Benatti U, De Flora A
Institute of Biochemistry, University of Genoa, Italy.
Proc Natl Acad Sci U S A. 1989 Mar;86(6):2040-4. doi: 10.1073/pnas.86.6.2040.
Doxorubicin-loaded, glutaraldehyde-treated murine erythrocytes, once reinjected into circulation, are rapidly taken up by liver and lungs and behave as an organ-targeted, slow delivery system for the encapsulated drug. The antitumor activity of encapsulated doxorubicin (former generic name, adriamycin) was compared with that of the free drug in a murine hepatic and pulmonary tumor model. This was obtained by intrasplenic injection of L1210 lymphoma cells followed by splenectomy. Different schedules of treatment of tumor-bearing mice with erythrocyte-encapsulated or free doxorubicin were investigated. The optimal schedule of treatment for free doxorubicin proved to be i.v. bolus administration on the day of splenectomy. Under these conditions, the dose producing 50% inhibition of metastatic growth in the liver, as measured by inhibition of 5-[125I]iodo-2'-deoxyuridine uptake 9 days after tumor induction, was 6.3 mg/kg for free doxorubicin and 0.48 mg/kg for the encapsulated drug. In these conditions pulmonary tumor development was even more efficiently prevented by encapsulated doxorubicin as compared with the free drug. The values of the therapeutic index (TI), defined as the ratio between the maximal tolerated dose (LD10) and the minimal effective dose (ED90, producing 90% inhibition of liver metastatic growth), were 4.2 and 1.8 for encapsulated and free doxorubicin, respectively.
负载阿霉素、经戊二醛处理的小鼠红细胞，一旦重新注入循环系统，会迅速被肝脏和肺摄取，并作为一种针对器官的、缓慢释放的包封药物递送系统。在小鼠肝肺肿瘤模型中，将包封的阿霉素（原通用名，阿霉素）的抗肿瘤活性与游离药物的抗肿瘤活性进行了比较。这是通过脾内注射L1210淋巴瘤细胞，然后进行脾切除术来实现的。研究了用红细胞包封的阿霉素或游离阿霉素治疗荷瘤小鼠的不同方案。游离阿霉素的最佳治疗方案被证明是在脾切除当天静脉推注给药。在这些条件下，通过在肿瘤诱导后9天抑制5-[125I]碘-2'-脱氧尿苷摄取来测量，产生50%肝转移生长抑制的游离阿霉素剂量为6.3mg/kg，包封药物的剂量为0.48mg/kg。在这些条件下，与游离药物相比，包封的阿霉素能更有效地预防肺肿瘤的发展。治疗指数（TI）定义为最大耐受剂量（LD10）与最小有效剂量（ED90，产生90%肝转移生长抑制）之比，包封的阿霉素和游离阿霉素的治疗指数分别为4.2和1.8。
