Although the MEMs are rapidly developed their applications i

Although the MEMs are rapidly developed, their applications in prodrug activation are relatively less. In fact, the prodrug activation depending on the MEMs belongs to bioorthogonal chemistry [59], [60], [61], [62], [63], [64], [65], [66], which is an emerging area. On the other hand, many factors comprising their cell toxicity, catalytic rate as well as the matching between MEMs and prodrugs need to be comprehensively considered before using them. Nevertheless, recent progresses in prodrug activation and pro-fluorescence activation mediated by MEMs are inspiring and we believe that this strategy has the potential for improving traditional EAPT, serving as the complement of natural enzymes. In this review, we first summarize the types of MEMs according to their structure and composition. Furthermore, considering that most prodrugs are activated by hydrolyzation and/or oxidoreduction of natural enzymes, we highlight the recent development for prodrug activation depending on hydrolase-like and oxidoreductase-like MEMs. We also summarize the potential prodrug activation mediated by some categories of MEMs corresponding to natural enzyme prodrug activation. In addition, the activations of pro-fluorescence Nystatin simulating prodrugs are together discussed, owing to their potential consistency with prodrug activation.
Categories of metal-contained enzyme mimics According to the MEMs\' structure and composition, there are three categories of MEMs: catalytic core-scaffold MEM (the catalytic cores include metal complexes, metal nanoparticles and functional molecules), nanoparticle MEM and metal-organic framework (MOF) MEM, which can be shorten as csMEM, npMEM and mofMEM, respectively. Herein, some representative MEMs with concrete characteristics are listed in Table 1.
Hydrolase-like MEM for prodrug activation Hydrolase-mediated prodrug activation is the most potential way for EAPT and has been widely researched in practical applications [15]. The key step of hydrolase-mediated prodrug activation is to cleave the chemical bond linking drug and promoiety for activating corresponding prodrugs (Fig. 2A). So far, different types of promoieties depending on the hydrolase-like MEMs have been developed, including allyloxycarbonyl promoiety (Fig. 2B), propargyl promoiety (Fig. 2C), propargyloxycarbonyl promoiety (Fig. 2D), tertiary propargyloxycarbonyl promoiety (Fig. 2E). In addition, some metal complexes potential for serving as the csMEMs\' catalytic core are included in this summary. Considering that the pro-fluorescent molecules are usually used as the models of prodrugs, their activation is the equivalent of prodrug activation. On the other hand, according to the mechanism of hydrolytic activation, the esterase mimics are believed to have strong potential for mediating the prodrug activation because natural esterases have been widely used in prodrug activation and the design of esterase mimics are well studied. Therefore, the MEMs mimicking natural esterases are also discussed in detail in this review.