Programmed Drug Release from Triple Stimuli-Responsive Poly( N -vinylcaprolactam)- b -Poly(ε-caprolactone) Copolymer Nanoassemblies with Enhanced Encapsulation through Noncovalent Interactions in the Core

Multi-stimuli-responsive biodegradable polymeric nanoassemblies with high encapsulation ability, micellar stability, and programmed intracellular drug release are highly attractive for efficient cancer therapy. Herein, an amphiphilic diblock copolymer responsive to three endogenous stimuli of a cancer cell is synthesized using temperature-responsive poly(N-vinylcaprolactam) as a macroinitiator for the ring-opening polymerization of chloroalkyl-substituted ε-caprolactone. Phenyl and triazole rings are incorporated in the side chain to link a redox-responsive disulfide group to a hydrophobic block using click chemistry. The diblock copolymer self-assembles in aqueous medium into spherical micelles with an average hydrodynamic diameter of 140–150 nm. High dye encapsulation efficiency and stability are verified by fluorescence resonance energy transfer and isothermal titration calorimetry studies. Copolymer nanoassemblies display ill-defined aggregates at tumor-relevant temperatures (40–43 °C), glutathione-induced swelling, and esterase-mediated complete micellar disassembly. Combined effect of triple stimuli on drug release is observed compared to the release in response to individual stimuli. The diblock copolymer shows excellent biocompatibility with MCF-7 and MDA-MB-231 cancer cells, and DOX-loaded copolymer nanoassemblies show cytotoxicity toward the cancer cells, augmented by low IC50 values (6.37 and 4.58 μg/mL). Cellular uptake and time-dependent drug release in cancer cells are demonstrated.