Nano-sized assemblies of a PEG-docetaxel conjugate as a formulation strategy for docetaxel.

An amphiphilic polymer-drug conjugate was prepared by attachment of low molecular weight methoxy poly(ethylene glycol) (PEG) (i.e., 2 kDa) to docetaxel (DTX) through an ester linkage. The PEG-DTX conjugate having a critical micelle concentration of 0.88 mg/mL was used to form nano-sized micelles, with mean diameters of less than 100 nm, for solubilization of free DTX. The maximum concentrations of free and conjugated DTX achieved in this formulation were 28 and 12 mg/mL (DTX equivalent), respectively; which corresponds to a drug to polymer ratio of 4:3 (w/w). The physico-chemical properties of the PEG-DTX conjugate and DTX formulation were evaluated including stability, rate of hydrolysis, hemolytic activity, and drug release profile. The anti-cancer activity of the drug in the PEG-DTX micelle formulation was demonstrated to be retained in three human cancer cell lines. Intravenous administration of DTX in the PEG-DTX micelles revealed relatively rapid dissociation of the free drug from the formulation; however, a 1.8-fold higher DTX equivalent area under the plasma concentration-time curve (AUC) was obtained, in comparison to DTX administered as Taxotere. The maximum tolerated dose of this DTX formulation was also 2.5-fold higher than that for Taxotere(R) in healthy mice.