Kim C K, Han J H
College of Pharmacy, Seoul National University, Korea.
J Microencapsul. 1995 Jul-Aug;12(4):437-46. doi: 10.3109/02652049509087256.
The lymph node targeting ability and pharmacokinetics of methotrexate (MTX) after intramuscular (i.m.) injection of differently charged liposome-entrapped [3H]MTX to rats were evaluated using [3H]MTX as a tracer. Neutral liposomes were prepared with a mixture of phosphatidylcholine, cholesterol and alpha-tocopherol (8:4:0.1, molar ratio). Positively and negatively charged liposomes were also prepared by incorporation of stearylamine (8:4:0.1, molar ratio) and dicetylphosphate (8:4:0.1:1, molar ratio) into neutral liposomes respectively. The encapsulation efficiency (as expressed in terms of radioactivity) in liposomes was increased as alpha-tocopherol was incorporated into the lipid bilayer. The disappearance of [3H]MTX from the i.m. injection site was rapid and essentially complete after 30 min. On the other hand, the disappearance of radioactivity of liposome-entrapped [3H]MTX was much slower when compared to free drug. The area under the drug concentration-time curve (AUC) of liposome-entrapped [3H]MTX in lymph nodes was significantly increased when compared to free [3H]MTX. It suggested that liposomes injected by the i.m. route entered into the lymphatics and only drug released from liposomes diffused directly into the systematic circulation. The liposome-entrapped [3H]MTX by i.m. route was markedly localized in the lymph nodes. The concentration of MTX-equivalents in regional lymph node after i.m. injection of liposome-entrapped [3H]MTX was > 100-350 fold higher when compared to the plasma concentration. These values are more than 10-20 fold higher compared to the i.m. injection of free [3H]MTX. The positively charged liposomes were more localized in lymph nodes compared to neutral and negatively charged ones. While liposomes injected by i.v. route were localized in liver, spleen and lung compared to free [3H]MTX, it was evident that i.m. administration of liposomes resulted in enhanced localization of MTX in the lymphatic system but decreased deposition in kidney, liver and other non-targeting tissues compared to free [3H]MTX. The targeting ability and carrier properties of liposome-entrapped anticancer drugs with varying surface charge, lipid compositions and route of administration are of significant importance to alter biodistribution in chemotherapy.
以[³H]甲氨蝶呤（MTX）为示踪剂，评估大鼠肌肉注射不同电荷脂质体包裹的[³H]MTX后，MTX的淋巴结靶向能力和药代动力学。中性脂质体由磷脂酰胆碱、胆固醇和α-生育酚（摩尔比8:4:0.1）混合制备。通过分别将硬脂胺（摩尔比8:4:0.1）和二鲸蜡基磷酸酯（摩尔比8:4:0.1:1）掺入中性脂质体中，还制备了带正电荷和负电荷的脂质体。随着α-生育酚掺入脂质双层，脂质体中的包封率（以放射性表示）增加。肌肉注射部位的[³H]MTX在30分钟后迅速消失且基本完全消失。另一方面，与游离药物相比，脂质体包裹的[³H]MTX的放射性消失要慢得多。与游离[³H]MTX相比，脂质体包裹的[³H]MTX在淋巴结中的药物浓度-时间曲线下面积（AUC）显著增加。这表明通过肌肉注射途径注入的脂质体进入淋巴管，只有从脂质体中释放的药物直接扩散到体循环中。通过肌肉注射途径的脂质体包裹的[³H]MTX明显定位于淋巴结。肌肉注射脂质体包裹的[³H]MTX后，区域淋巴结中MTX等效物的浓度比血浆浓度高100 - 350倍以上。这些值比肌肉注射游离[³H]MTX高10 - 20倍以上。与中性和带负电荷的脂质体相比，带正电荷的脂质体在淋巴结中的定位更多。虽然静脉注射途径的脂质体与游离[³H]MTX相比定位于肝脏、脾脏和肺，但很明显，与游离[³H]MTX相比，肌肉注射脂质体导致MTX在淋巴系统中的定位增强，但在肾脏、肝脏和其他非靶向组织中的沉积减少。脂质体包裹的具有不同表面电荷、脂质组成和给药途径的抗癌药物的靶向能力和载体特性对于改变化疗中的生物分布具有重要意义。
