Enzyme‐Responsive Micelles with High Drug‐Loading Capacity for Antitumor Therapy

Abstract To overcome the poor targeting of conventional chemotherapeutic drugs and the defects of low drug‐loading capacity of conventional drug delivery systems, novel drug delivery systems with high drug‐loading capacity are developed. Herein, the high drug‐loaded mPEG 79 ‐GFLGDDD‐DOX copolymer is first synthesized via an amide reaction, which can bond multiplex DOX. After PEGylation, the drug can resist the adsorption of proteins in the plasma in blood circulation, avoid being rapidly cleared out of the body, and prolong the circulation time of the drug in the blood, which is conducive to the enrichment of micelles in tumor tissues through the EPR effect. In tumor tissues, the peptide Glycine‐ Phenylalanine‐ Leucine‐ Glycine (GFLG) is recognized and sheared by overexpressed cathepsin B, which stripped the outer layer of methoxy polyethylene glycol (mPEG) and made it more readily available for uptake by tumor cells. After entering the tumor cells, the bonded DOX and the physically encapsulated DOX in the micelles played a synergistic role, realizing the killing of tumor cells, thus effectively enhancing the therapeutic effect on tumors. The findings in this work suggest that a high drug‐loading drug delivery system has great potential in the clinical treatment of tumors.