Enzyme and Redox Dual-Triggered Intracellular Release from Actively Targeted Polymeric Micelles.

Highly effective delivery of therapeutic agents into target cells using nanocarriers and subsequently rapid intracellular release are of great importance in cancer treatment. Here, we developed an enzyme and redox dual-responsive polymeric micelle with active targeting abilities to achieve rapid intracellular drug release. To overcome both its poor solubility in water and instability in the blood circulation, camptothecin (CPT) was chemically conjugated to monomethyl poly(ethylene glycol) (mPEG) via a redox-responsive linker to form polymeric prodrugs. The enzyme-responsive function is achieved by connecting hydrophobic polycaprolactone segments and hydrophilic PEG segments with azo bonds. Additionally, the end of the PEG segment was decorated with phenylboronic acid (PBA), endowing the nanocarriers with active targeting abilities. The dual-responsive targeting polymeric micelles can be generated by self-assembly of a mixture of the polymeric prodrug and enzyme-responsive copolymer. The in vitro drug release profile revealed that CPT was rapidly released from the micelles under a simulated condition similar to the tumor cell microenvironment. In vivo and ex vivo fluorescence imaging indicated that these micelles possess excellent specificity to target hepatoma carcinoma cells. The antitumor effect in mice liver cancer cells (H22) in tumor-bearing Kunming (KM) mice demonstrated that this nanocarrier exhibits high therapeutic efficiency in artificial solid tumors and low toxicity to normal tissues, with a survival rate of approximately 100% after 160 days of treatment.