An Enzyme-Responsive And Redox-Responsive Micellar System For Effective Cancer Treatment

Highly effective delivery of therapeutic agents with micelles into target cells and subsequently rapid intracellular release are of great importance in cancer treatment. This is due to the fact that the micelles can increase the drug-loading efficiency, improve the hydrophobic drug solubility, prolong the circulation of drugs in the blood system and reduce the side effects of drugs on normal tissue. However, how to improve the accumulation of nanoparticles in tumor site is still a great challenge. Accordingly, in this study we develop an enzyme and redox dual-responsive polymer micelles system simultaneously with actively targeting ability for achieving rapid intracellular drug release in cancer treatment.To overcome both the poor solubility in water and instability in the circulation of the blood, camptothecin (CPT) is chemically conjugated to monomethyl poly (ethylene glycol) (mPEG) via redox-responsive linkers to form prodrug (mPEG-ss-CPT). The enzyme-responsive function is achieved by connecting the hydrophobic polycaprolactone (PCL) segments and hydrophilic poly (ethylene glycol) (PEG) segments with azo bonds into an amphiphilic copolymer (PBA-PEG-Azo-PCL). Simultaneously, the end of PEG segment is decorated with phenylboronic acid (PBA), endowing the nanocarriers with an actively targeting ability. Next we fabricated the prodrug into the polymer micelles (PBA-PEG-Azo-PCL/mPEG-ss-CPT) by the solvent evaporation method to prepare the enzyme and redox-responsive micelles with actively targeting ability. The properties of materials and micelles were demonstrated by 1H NMR, GPC, DLS and TEM evaluation.Then, we stimulated physiological environment of human for in vitro drug release study. We mainly inspected the drug cumulative release of micelles which were incubated in the presence of azo reductase, co-enzyme reduced nicotinamide adenine dinucleotide phosphate (NADPH) and glutathione (GSH) in 48 hours. In vitro cytotoxicity experiment result demonstrated that the enzyme-responsive micelles had good biocompatibility, and the drug-loading micelles can inhibit the growth of cancer cells due to the fact that the micelles could be specifically internalized into tumor cells and then the CPT was promptly released in cytoplasm in response to a high level of GSH.Lastly, in vivo and ex vivo fluorescence imaging displayed that these micelles possessed excellent specificity to target hepatoma carcinoma cells. The antitumor effect in H22 tumor-bearing Kunming mice demonstrated that the PBA-PEG-Azo-PCL/mPEG-ss-CPT has a high therapeutic efficiency to the tumor.