title: 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 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.
authors.affiliation: Pharmaceutical Sciences Division, School of Pharmacy, University of Wisconsin, 777 Highland Avenue, Madison, WI 53705, USA.
authors.forename: Ho-Chul
authors.initials: HC
authors.lastname: Shin
authors.forename: Hyunah
authors.initials: H
authors.lastname: Cho
authors.forename: Tsz Chung
authors.initials: TC
authors.lastname: Lai
authors.forename: Kevin R
authors.initials: KR
authors.lastname: Kozak
authors.forename: Jill M
authors.initials: JM
authors.lastname: Kolesar
authors.forename: Glen S
authors.initials: GS
authors.lastname: Kwon
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000971:Antineoplastic Combined Chemotherapy Protocols; D019540:Area Under Curve; D016227:Benzoquinones / Q000008:administration & dosage / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D004337:Drug Carriers / Q000008:administration & dosage / Q000493:pharmacokinetics*; D004338:Drug Combinations; D005260:Female; D047029:Lactams, Macrocyclic / Q000008:administration & dosage / Q000493:pharmacokinetics*; D007773:Lactates / Q000008:administration & dosage / Q000493:pharmacokinetics*; D051379:Mice; D008823:Micelles; D017239:Paclitaxel / Q000008:administration & dosage / Q000493:pharmacokinetics*; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000493:pharmacokinetics*; D020123:Sirolimus / Q000008:administration & dosage / Q000493:pharmacokinetics*
chemical_list: D000970:Antineoplastic Agents; D016227:Benzoquinones; D004337:Drug Carriers; D004338:Drug Combinations; D047029:Lactams, Macrocyclic; D007773:Lactates; D008823:Micelles; C088513:poly(lactic acid-ethylene glycol); D011092:Polyethylene Glycols; C112765:tanespimycin; D017239:Paclitaxel; D020123:Sirolimus