Miyamoto M, Hirano K, Ichikawa H, Fukumori Y, Akine Y, Tokuuye K
Faculty of Pharmaceutical Sciences, Kobe Gakuin University, Japan.
Biol Pharm Bull. 1999 Dec;22(12):1331-40. doi: 10.1248/bpb.22.1331.
Emulsions containing a distearylamide (Gd-DTPA-SA) or a distearylester (Gd-DTPA-SE) of Gd (gadolinium)-diethylenetriaminepentaacetic acid (Gd-DTPA) were intraperitoneally injected in Greene's melanoma-bearing hamsters at a dose of 2.0 ml (3.0 or 6.0 mg Gd) per hamster. In the standard-Gd and high-Gd formulations used, the weight ratios of soybean oil, water, Gd-DTPA derivative (Gd-DTPA-SA or Gd-DTPA-SE), hydrogenated L-alpha-phosphatidylcholine from egg yolk (HEPC) and co-surfactant (HCO-60, Myrj 53, Myrj 59 or Brij 700) were 7.36:92:1:2:3 and 7.36:92:2:1:3, respectively. When the effects of the co-surfactants on the biodistribution of Gd from Gd-DTPA-SA-containing emulsions in the standard-Gd formulation were compared, the HCO-60 emulsion exhibited the highest Gd accumulation in tumors, possibly resulting from its fast and complete absorption, its small particle size (78 nm) and the stable coat on the particle surfaces with polyoxyethylene. Brij 700 emulsion kept the highest blood Gd concentration for a prolonged period, possibly due to particle properties similar to those of HCO-60. However, it exhibited a slower Gd accumulation in tumors, only reaching an identical level, in comparison with the HCO-60 emulsion. This suggested the tumor to be saturated with lipid particles. When Gd-DTPA-SE was used instead of Gd-DTPA-SA, its HCO-60 emulsion exhibited only very poor Gd-accumulation due to its easy degradation. The HCO-60 emulsion particles containing Gd-DTPA-SA in the high-Gd formulation (6.0 mg Gd in 2 ml) exhibited in vivo behavior identical to those in the standard-Gd formulation; then the Gd level in tumors reached 107 micrograms Gd/g tumor (wet), and the tumor:blood (T/B) and tumor:skin (T/Sk) Gd concentration ratios were 13.2 and 5.6, respectively, at 48 h after intraperitoneal administration. These results suggest that when intraperitoneally administered, this HCO-60 emulsion, and possibly also the corresponding Brij 700 emulsion, may be an excellent delivery system for accumulating Gd in tumors in neutron-capture therapy (NCT).
将含有钆（Gd）-二乙烯三胺五乙酸（Gd-DTPA）的双硬脂酰胺（Gd-DTPA-SA）或双硬脂酸酯（Gd-DTPA-SE）的乳剂以每只仓鼠2.0毫升（3.0或6.0毫克钆）的剂量腹腔注射到患有格林氏黑色素瘤的仓鼠体内。在所使用的标准钆制剂和高钆制剂中，大豆油、水、Gd-DTPA衍生物（Gd-DTPA-SA或Gd-DTPA-SE）、蛋黄氢化L-α-磷脂酰胆碱（HEPC）和辅助表面活性剂（HCO-60、聚山梨醇酯53、聚山梨醇酯59或月桂醇聚醚700）的重量比分别为7.36:92:1:2:3和7.36:92:2:1:3。当比较辅助表面活性剂对标准钆制剂中含Gd-DTPA-SA乳剂中钆生物分布的影响时，HCO-60乳剂在肿瘤中的钆积累量最高，这可能是由于其快速且完全的吸收、较小的粒径（78纳米）以及颗粒表面由聚氧乙烯形成的稳定包衣。月桂醇聚醚700乳剂在较长时间内保持最高的血液钆浓度，这可能是由于其颗粒性质与HCO-60相似。然而，与HCO-60乳剂相比，它在肿瘤中的钆积累较慢，仅达到相同水平。这表明肿瘤被脂质颗粒饱和。当使用Gd-DTPA-SE代替Gd-DTPA-SA时，其HCO-60乳剂由于易于降解，钆积累非常差。高钆制剂（2毫升中含6.0毫克钆）中含Gd-DTPA-SA的HCO-60乳剂颗粒在体内的行为与标准钆制剂中的相同；腹腔给药后48小时，肿瘤中的钆水平达到107微克钆/克肿瘤（湿重），肿瘤与血液（T/B）以及肿瘤与皮肤（T/Sk）钆浓度比分别为13.2和5.6。这些结果表明，腹腔给药时，这种HCO-6乳剂以及可能相应的月桂醇聚醚700乳剂，可能是在中子俘获治疗（NCT）中使钆在肿瘤中积累的优良递送系统。
