Mori A, Kennel S J, van Borssum Waalkes M, Scherphof G L, Huang L
Department of Pharmacology, University of Pittsburgh School of Medicine, PA 15261.
Cancer Chemother Pharmacol. 1995;35(6):447-56. doi: 10.1007/BF00686828.
A previous study has shown that lipophilic prodrugs can be delivered efficiently to normal lung endothelium by incorporation into liposomes covalently conjugated to monoclonal antibody (mAb) 34A against the lung endothelial anticoagulant protein thrombomodulin. In the present study, the potential use of these lung-targeted immunoliposomes (34A-liposomes) for delivery of a lipophilic prodrug, 3',5'-O-dipalmitoyl-5-fluoro-2'-deoxyuridine (dpFUdR), to the tumor-bearing lung was examined using BALB/c mice bearing experimental lung metastasis induced by i.v. injection of EMT-6 mouse mammary tumor cells. Immunohistochemical examination of the tumor-bearing lung showed specificity of mAb 34A to lung endothelium. Tumor cells appeared to localize just outside of the normal blood vessels and were within a small diffusion distance from the mAb 34A-binding sites. 111In-labeled 34A-liposomes containing monosialoganglioside (GM1) were prepared that included [3H]-dpFUdR at 3.0 mol% in the lipid mixture. In vitro cell binding studies further demonstrated that 34A-liposomes bound specifically to normal mouse lung cells that expressed thrombomodulin but not to EMT-6 cells. Biodistribution study showed efficient and immunospecific accumulation of [3H]-dpFUdR incorporated into 34A-liposomes in the lung at a level parallel with that of 111In-labeled 34A-liposomes, indicating that the drug is delivered to the target organ in intact liposomes. Liposomal dpFUdR appeared to be metabolized in the lung to the parent drug FUdR at a rate slower than in the liver and spleen. Furthermore, treatment of lung-metastasis-bearing mice with dpFUdR incorporated into 34A-liposomes on days 1 and 3 after tumor cell injection resulted in a significant increase in the median survival time of treated mice as compared with control mice (%T/C value, 165%). dpFUdR either dispersed in emulsion or incorporated into antibody-free liposomes was ineffective in prolonging the survival of mice. These results indicate the potential effectiveness of organ-specific immunoliposomes containing a lipophilic prodrug for the targeted therapy of metastatic tumors.
先前的一项研究表明，通过将亲脂性前药掺入与抗肺内皮抗凝蛋白血栓调节蛋白的单克隆抗体（mAb）34A共价偶联的脂质体中，可将其有效地递送至正常肺内皮细胞。在本研究中，使用经静脉注射EMT-6小鼠乳腺肿瘤细胞诱导产生实验性肺转移的BALB/c小鼠，研究了这些肺靶向免疫脂质体（34A-脂质体）用于将亲脂性前药3',5'-O-二棕榈酰-5-氟-2'-脱氧尿苷（dpFUdR）递送至荷瘤肺的潜在用途。对荷瘤肺的免疫组织化学检查显示mAb 34A对肺内皮细胞具有特异性。肿瘤细胞似乎定位在正常血管之外，且与mAb 34A结合位点的扩散距离较小。制备了含有单唾液酸神经节苷脂（GM1）的111In标记的34A-脂质体，脂质混合物中[3H]-dpFUdR的含量为3.0 mol%。体外细胞结合研究进一步表明，34A-脂质体特异性结合表达血栓调节蛋白的正常小鼠肺细胞，而不与EMT-6细胞结合。生物分布研究表明，掺入34A-脂质体中的[
