Remote loading of preencapsulated drugs into stealth liposomes

Significance Nanoliposomal packaging of chemotherapeutics can increase efficacy while reducing toxicity, but its use is currently limited due to inefficient loading strategies. We developed an active loading procedure by designing a transient chemical handle for ferrying such agents into preformed liposomes. We illustrate its use with two candidates that recently failed phase II studies. We were able to load both these drugs into liposomes with high efficiency and administer them to animals at substantially higher doses than previously possible, thereby simultaneously enhancing efficacy and reducing toxicity. This strategy should be applicable to many agents that are currently being developed to treat cancer or other diseases, and can “rescue” drugs that would otherwise fail at the final stages of the drug discovery process. 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.