Self-assembly behavior of thermoresponsive difunctionalized γ-amide polycaprolactone amphiphilic diblock copolymers

Polycaprolactone (PCL)-based polymeric micelles are extensively used as drug delivery carriers to improve the bioavailability of poorly water soluble drugs due to their convenient tunability by varying functional groups on the polymers. An amide linkage enables the attachment of two different functional groups to the same position of PCLs, expanding the family of functional PCLs for drug delivery applications. In this work, a difunctionalized gamma-amide epsilon-caprolactone (epsilon-CL) monomer (gamma-ME3PyCL) bearing a hydrophilic tri(ethylene glycol) (ME3) group and a hydrophobic propyl group was synthesized. A homopolymer poly(N-propyl-N-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)-7-oxoxepane-4-carboxamide) PME3PyCL and three amphiphilic diblock copolymers poly(gamma-benzyloxy-epsilon-caprolactone)-b-poly(N-propyl-N-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)-7-oxoxepane-4-carboxamide) (PBnCL-b-PME3PyCL), polycaprolactone-b-poly(N-propyl-N-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)-7-oxoxepane-4-carboxamide) (PCL-b-PME3PyCL), and polycaprolactone-b-poly(gamma-2-(2-(2-methoxyethoxy)ethoxy)ethoxy-epsilon-caprolactone) (PCL-b-PME3CL) were prepared by ring opening polymerization (ROP) using the organocatalyst triazabicylo[4.4.0]dec-5-ene (TBD) and benzyl alcohol (BnOH) initiator. The ME3 group contributes to the thermoresponsivity of the polymers. The diblock copolymer PBnCL-b-PME3PyCL exhibited the most stable reversible phase transition due to enhanced pi-pi stacking interactions from the benzyl groups. All three diblock copolymers formed thermodynamically stable spherical micelles with low critical micelle concentration. A natural polyphenol, quercetin (Que) was used as hydrophobic cargo for loading. Among the three diblock polymers, PBnCL-b-PME3PyCL exhibited the highest loading capacity due to enhanced pi-pi interactions between benzyl groups and Que.