Improved Drug Delivery through Amide-Functionalized Polycaprolactones: Enhanced Loading Capacity and Sustained Drug Release

Polymeric micelles are effective for drug delivery but often face instability, low drug loading capacity (DLC), and premature drug leakage. Herein, we report that disubstituted γ-amide functionalized ε-caprolactone (ε-CL) monomers double the substituent density per polymeric unit, enhancing micelle properties and improving drug delivery applications. Three hydrophobic ε-CL monomers with two propyl groups, two benzyl groups, and a combination of propyl and benzyl groups were synthesized. The obtained monomers were polymerized by ring-opening polymerization using poly(ethylene glycol) (PEG) as a macroinitiator and the hydrophilic block. The synthesized copolymers successfully self-assembled to form micelles, and doxorubicin (DOX) was loaded into all micelles. Poly(ethylene glycol)<i>-b-</i>poly(<i>N</i>-propyl-<i>N</i>-benzyl-7-oxopane-4-carboxamide) (PEG<i>-b-</i>PBnPyCL) exhibited 7.33 wt % DLC with pH-responsive drug release in acidic conditions. In addition, the DOX-loaded micelles of PEG-<i>b</i>-PBnPyCL exhibited nearly 20% cell viability in MDA-MB-231 cancer cells. These results contribute to advancing polymeric micelles as drug carriers with clinical translation potential.