Paclitaxel prodrugs with sustained release and high solubility in poly(ethylene glycol)-b-poly(ε-caprolactone) micelle nanocarriers:: Pharmacokinetic disposition, tolerability, and cytotoxicity

Purpose. Develop a Cremophor((R)) and solvent free formulation of paclitaxel using amphiphilic block co-polymer micelles of poly(ethylene glycol)-b-poly(epsilon-caprolactone) (PEG-b-PCL) and characterize their release, solubility, cytotoxicity, tolerability, and disposition. Methods. Hydrophobic prodrugs of paclitaxel were synthesized via DCC/DMAP or anhydride chemistry to overcome the poor loading (< 1% w/w) of paclitaxel in micelles of PEG-b-PCL. Micelles were prepared by a co-solvent extraction technique. A micellar formulation of paclitaxel prodrug (PAX7'C-6) was dosed intravenously to rats (10 mg/kg) and compared to Taxol((R)) (paclitaxel in CrEL:EtOH) and PAX7'C-6 in CrEL:EtOH as controls at the same dose. Pharmacokinetic parameters and tissue distribution were assessed. Results. Paclitaxel prodrugs had solubilities > 5 mg/ml in PEG-b-PCL micelles. Resulting PEG-b-PCL micelles contained 17-22% w/w prodrug and were less than 50 nm in diameter. PEG-b-PCL micelles released paclitaxel prodrugs over several days, t(1/2)> 3 d. Only the 7'derivative of paclitaxel with the shortest acylchain 7'hexonoate (PAX7'C-6) maintained cytotoxic activity similar to unmodified paclitaxel. PAX7'C-6 micelles demonstrated an increase in area under the curve, half-life, and mean residence time while total clearance and volume of distribution decreased. Conclusions. Paclitaxel prodrugs in PEG-b-PCL micelle nanocarriers augment the disposition and increase tolerability making further studies on tumor efficacy warranted.