Ludwig Center and Howard Hughes Medical Institute, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21231.
Proc Natl Acad Sci U S A. 2014 Feb 11;111(6):2283-8. doi: 10.1073/pnas.1324135111. Epub 2014 Jan 28.
Loading drugs into carriers such as liposomes can increase the therapeutic ratio by reducing drug concentrations in normal tissues and raising their concentrations in tumors. Although this strategy has proven advantageous in certain circumstances, many drugs are highly hydrophobic and nonionizable and cannot be loaded into liposomes through conventional means. We hypothesized that such drugs could be actively loaded into liposomes by encapsulating them into specially designed cyclodextrins. To test this hypothesis, two hydrophobic drugs that had failed phase II clinical trials because of excess toxicity at deliverable doses were evaluated. In both cases, the drugs could be remotely loaded into liposomes after their encapsulation (preloading) into cyclodextrins and administered to mice at higher doses and with greater efficacy than possible with the free drugs.
将药物载入载体（如脂质体）中可以通过降低正常组织中的药物浓度并提高肿瘤中的药物浓度来提高治疗比率。尽管这种策略在某些情况下已经证明是有利的，但许多药物具有高度疏水性和非离子化特性，无法通过常规方法载入脂质体中。我们假设可以通过将这些药物包封在专门设计的环糊精中来主动载入脂质体。为了验证这一假设，我们评估了两种因在可给药剂量下毒性过高而在 II 期临床试验中失败的疏水性药物。在这两种情况下，这些药物可以在包封（预载）到环糊精后远程载入脂质体中，并以比游离药物更高的剂量和更高的疗效给予小鼠。
