Pharmacokinetic study of 3-in-1 poly(ethylene glycol)-block-poly(D L-lactic acid) micelles carrying paclitaxel 17-allylamino-17-demethoxygeldanamycin and rapamycin

摘要

Concurrent delivery of multiple poorly water-soluble anticancer drugs has been a great challenge due to the toxicities exerted by different surfactants or organic solvents used in solubilizing individual drugs. We previously found that poly(ethylene glycol)-block-poly(D, L-lactic acid) (PEG-b-PLA) micelles can serve as a safe delivery platform for simultaneous delivery of paclitaxel (PTX), 17-allylamino-17-demethoxygeldanamycin (17-AAG), and rapamycin (RAP) to mice. The high tolerance of this polymeric micelle formulation by mice allowed us to investigate the pharmacokinetics of the 3 co-delivered drugs. In this study, it was shown that 3-in-1 PEG-b-PLA micelle delivering high doses of PTX, 17-AAG, and RAP (60, 60, and 30 mg/kg, respectively) significantly increased the values of the area under the plasma concentration-time curves (AUC) of PTX and RAP in mice compared to the drugs delivered individually, while the pharmacokinetic parameters of 17-AAG were similar in both 3-in-1 and single drug-loaded PEG-b-PLA micelle formulations. Moreover, pharmacokinetic study using 2-in-1 micelles indicated that the augmented AUC value of RAP was due to the co-delivery of 17-AAG, while the increase in AUC of PTX was more likely caused by the co-delivery of RAP. In contrast, when 3-in-1 and single drug-loaded PEG-b-PLA micelles were administrated at modest dose (PTX, 17-AAG, and RAP at 10, 10, and 5 mg/kg, respectively), pharmacokinetic differences of individual drugs between 3-in-1 and single drug formulations were eliminated. These results suggest that 3-in-1 PEG-b-PLA micelles can concurrently deliver PTX, 17-AAG, and RAP without changing the pharmacokinetics of each drug at modest doses, but altered pharmacokinetic profiles emerge when drugs are delivered at higher doses.