Engineering Poly(ε-caprolactone)-Based Maleimide-Enediyne Micelles for Next-Generation Anticancer Therapies.

Inspired by the DNA-cleaving potency of natural enediynes such as calicheamicin, we report the design and synthesis of maleimide-enediyne conjugates integrated into poly(ε-caprolactone) (PCL) as a next-generation platform for anticancer drug delivery. Maleimide-based enediynes typically suffer from poor aqueous solubility and nonspecific toxicity, addressed here by covalently incorporating enediyne groups into amphiphilic PCL block copolymers via post-polymerization functionalization. The resulting polymers form ∼120 nm spherical micelles with a critical micelle concentration of 9.1 × 10-4 mg mL-1, enhancing enediyne solubility, promoting tumor accumulation through the EPR effect, and enabling encapsulation of hydrophobic drugs such as doxorubicin. Electron paramagnetic resonance confirmed radical formation and Bergman cyclization under physiological conditions. Cell viability assays showed enediyne-induced death in MDA-MB-231 breast cancer cells, and the functionalized PCL exhibited in vitro DNA cleaving activity, demonstrating that maleimide-enediyne-functionalized PCL micelles are promising platforms for cancer chemotherapy.