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

Abstract

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 γ-amide ε-caprolactone (ε-CL) monomer (γ-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(γ-benzyloxy-ε-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(γ-2-(2-(2-methoxyethoxy)ethoxy)ethoxy-ε-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 π–π 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 π–π interactions between benzyl groups and Que.