LIPOSOME FORMULATIONS WITH PROLONGED CIRCULATION TIME IN BLOOD AND ENHANCED UPTAKE BY TUMORS
LIPOSOME FORMULATIONS WITH PROLONGED CIRCULATION TIME IN BLOOD AND ENHANCED UPTAKE BY TUMORS
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DOI：
10.1073/pnas.85.18.6949
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发表时间：
1988-09-01
影响因子：
11.1
通讯作者：
PAPAHADJOPOULOS, D
中科院分区：
文献类型：
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作者：
GABIZON, A;PAPAHADJOPOULOS, D
循环脂质体从血流中的快速清除，加上它们被肝脏和脾脏的高摄取，迄今为止一直是靶向肿瘤的任何尝试的障碍。我们已经评估了脂质体组合物对它们在正常和荷瘤小鼠中从循环中清除以及对它们被肿瘤和各种正常组织摄取的影响。通过选择性改变脂质组成，同时保持平均粒径约为100 nm，我们已经实现了静脉注射后24小时血液中存在的回收剂量分数增加高达60倍。同时，网状内皮系统的主要器官肝脏和脾脏中的回收剂量降低了4倍。在荷瘤小鼠中的平行实验表明，当比较具有长和短血液停留时间的制剂时，肿瘤中的脂质体浓度增加了25倍。最有利的结果是获得与脂质体含有小摩尔分数的带负电荷的糖脂，如monosialoganglioside或phosphateidylinositol，和固相中性磷脂作为散装组分。这种制剂的生物分布在癌症中具有相当大的治疗潜力，用于增加肿瘤中细胞毒性剂的浓度，同时使对网状内皮系统的毒性的可能性最小化。
The rapid clearance of circulating liposomes from the bloodstream, coupled with their high uptake by liver and spleen, has thus far been an obstacle to any attempts at targeting to tumors. We have assessed the impact of liposome composition on their clearance from the circulation in normal and tumor-bearing mice and on their uptake by tumors and various normal tissues. By selective changes in lipid composition, while maintaining a mean particle diameter of .apprxeq. 100 nm, we have achieved up to a 60-fold increase in the fraction of recovered dose present in blood 24 hr after i.v. injection. Concomitantly, there was a decrease by a factor of 4 of the recovered dose localizing in the liver and spleen, the major organs of the reticuloendothelial system. Parallel experiments in tumor-bearing mice demonstrated a 25-fold increase of the liposome concentration in the tumor when formulations with long and short blood residence time were compared. The most favorable results were obtained with liposomes containing a small molar fraction of a negatively charged glycolipid, such as monosialoganglioside or phosphateidylinositol, and a solidphase neutral phospholipid as the bulk component. The biodistribution of such formulations is of considerable therapeutic potential in cancer for increasing the concentration of cytotoxic agents in tumors while minimizing the likeihood of toxicity to the reticuloendothelial system.