A Combined Experimental and Computational Study of the Substituent Effect on Micellar Behavior of γ-Substituted Thermoresponsive Amphiphilic Poly(ε-caprolactone)s

The effect of the core substituent structure on the micellar behavior of thermoresponsive amphiphilic poly(epsilon-caprolactone) diblock copolymer micelles was investigated through a combination of experimental and computational methods. The polycaprolactone (PCL) amphiphilic block copolymers used in this study consisted of a hydrophilic poly{gamma-2-[2-(2-methoxyethoxy)ethoxy]ethoxy-epsilon-caprolactone} block, which also endowed the polymer with thermoresponsiveness, and various hydrophobic poly(gamma-alkoxy-epsilon-caprolactone) blocks. Five different substituents have been attached to the gamma-position of the epsilon-caprolactone of the hydrophobic block, namely octyloxy, ethylhexyloxy, ethoxy, benzyloxy, and cyclohexylmethoxy, which self-assembled in aqueous media to generate the core of the micelles. All five synthesized diblock copolymers formed micelles in water and displayed thermoresponsive behavior with lower critical solution temperature (LCST) in the range of 36-39 degrees C. The impact of different substituents on the micelle properties such as size, stability, and phase transition behavior was investigated. Drug loading and release properties were also studied by employing doxorubicin (DOX) as payload. Molecular dynamics modeling was used to predict the variation of particle size, free volume, and drug loading capacity. The drug loading capacity predicted from molecular dynamics simulation was found to be comparable with the experimental data, which suggests that molecular dynamic simulations may be a useful tool to provide valuable selection criteria for the engineering of polymeric micelles with tunable size and drug loading capacity.