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

Abstract

The effect of the core substituent structure on the micellar behavior of thermoresponsive amphiphilic poly(εcaprolactone) 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{γ-2-[2-(2-methoxyethoxy)ethoxy]ethoxy-ε-caprolactone} block, which also endowed the polymer with thermoresponsiveness, and various hydrophobic poly(γ-alkoxy-ε-caprolactone) blocks. Five different substituents have been attached to the γ-position of the ε-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 °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.

Synthesis of linear and star-like poly(ε-caprolactone)-b-poly{γ-2-[2-(2-methoxy-ethoxy)ethoxy]ethoxy-ε-caprolactone} amphiphilic block copolymers using zinc undecylenate

“…In the case of poly{γ‐2‐[2‐(2‐methoxyethoxy)ethoxy]ethoxy‐ε‐caprolactone}, the addition of the oligo ethylene glycol substituent has been shown to afford hydrophilicity as well as thermoresponsivity . This biodegradable and biocompatible polymer can be used as the hydrophilic block in amphiphilic block copolymers that will self‐assemble in aqueous environments to form micelles for drug delivery applications.…”

“…Therefore, MEEECL offers the additional advantage of biodegradability through hydrolysis. Although MEEECL has been shown to have thermoresponsivity, the tunability of the lower critical solution temperature (LCST) is highly dependent on the hydrophobic portion of the block copolymer . Depending on the polymer used for the hydrophobic portion of the amphiphilic block copolymer, the LCST is not always in an appropriate range for biological applications.…”

HDAC inhibitor conjugated polymeric prodrug micelles for doxorubicin delivery

“…However, previous studies from our group revealed that the interaction between the drug and the polymer is more important than the void volume core in determining the drug loading capacity. 32 Therefore we have synthesized two different hydrophobic pendent groups featuring amphiphilic diblock copolymers with a substantial amount of PCL.…”

“…The size of copolymer micelles for P1 and P2 are larger than the previously reported values for amphiphilic block copolymers containing hydrophobic γ-substituted poly(ε-caprolactone)s despite the comparable molecular weights and ratios between the hydrophilic and hydrophobic blocks. 32, 33 The larger hydrodynamic size is most likely due to the bulky substituents which could result in an increase of the volume of the hydrophobic core. The sizes of micelles in TEM (transmission electron microscope) images were smaller than those measured by DLS (Fig.…”

Synthesis of well-defined carboxyl poly(ε-caprolactone) by fine-tuning the protection group

“…In order to overcome these limitations, many reactive groups, like hydroxyl, 6, 7 carboxylic 6, 8 and amino groups, 9,10 have been introduced onto the PCL chain with the aim for regulating its physico-chemical and biological properties, such as hydrophilicity, biodegradation rate and bioadhesion. 17,18 In the later approach, two issues containing monomer purity and deprotection feasibility as prerequisites ensure a successful synthesis. 12,13 Compared to postpolymerization modification strategy, [14][15][16] functional PCL prepared from its corresponding caprolactone monomer has exhibited better control over the pendant group substitution.…”