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

Abstract

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 30mg/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 5mg/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.