Copolymer Micelles and Nanospheres with Different In Vitro Stability Demonstrate Similar Paclitaxel Pharmacokinetics

Abstract

Paclitaxel loaded amphiphilic block copolymer nanoparticles have been demonstrated to enhance the aqueous solubility and improve the toxicity profile as compared to the commercially available product Taxol; however, in many cases long circulation of the drug is not achieved due to rapid partitioning of the drug from the carrier and/or carrier instability upon injection. In this work we investigated the effect of increasing the hydrophobic block length of methoxy poly(ethylene glycol)-block-poly(ε-caprolactone) (MePEG-b-PCL) copolymers on the physicochemical properties and in vitro stability of the formed nanoparticles as well as the pharmacokinetics and biodistribution of both the copolymer and solubilized drug. We hypothesized that copolymers composed of high molecular weight hydrophobic blocks (MePEG₁₁₄-b-PCL₁₀₄) that form nanoparticles with a kinetically "frozen core" (which we term nanospheres) would better retain their PTX payload as compared to micelles composed of shorter hydrophobic blocks (MePEG₁₁₄-b-PCL₁₉), thus leading to prolonged drug circulation. Nanospheres solubilized PTX more efficiently, released the drug in a more sustained fashion and were characterized by enhanced stability and drug retention in the presence of plasma proteins as compared to micelles. Using radiolabeled copolymers and PTX, it was found that, upon injection, MePEG₁₁₄-b-PCL₁₀₄ circulated for longer than MePEG₁₁₄-b-PCL₁₉; however, the drug was rapidly eliminated from the blood regardless of the formulation. These results suggest that, despite formulation in more stable nanospheres, PTX was still rapidly extracted from these nanoparticles.