Optimizing Combination Chemotherapy by Controlling Drug Ratios

The clinical application of drug–drug synergy depends on controlled delivery of the desired ratio to the in vivo target. In the upper panel, a drug cocktail is prepared at the desired ratio, but processes of drug distribution, metabolism, and excretion will act differentially upon the two drugs and cause the ratio to vary subsequent to injection. In this schematic, the two drugs distribute extensively and rapidly into tissues shortly after injection; note that the ratio of drugs that reaches the tumor has been displaced fivefold from the desired [injected (1:1)] ratio. In the lower panel, liposomes that contain the synergistic (1:1) ratio maintain and selectively deliver this drug ratio to the tumor. The appropriately designed drug delivery vehicles maintain the drugs in the blood at much higher concentrations for extended periods of time and, most importantly, at the effective, synergistic ratio. See text for details.