Enzyme mimics belong to a
Enzyme mimics belong to a type of rising catalysts which show the similar function with their corresponding natural enzymes , , , , , , , , although their structures are different from natural enzymes. In the area of prodrug activation, the widely-used enzyme mimics are mainly metal-contained enzyme mimics (MEMs) until now , , , , , . Compared with natural enzymes, the MEMs show many advantages for prodrug activation. First, the abiotic MEMs are more stable and easier to be stored than natural enzymes in complicated environment , which is convenient for serving as prodrug activation agents. Second, MEMs can be facilely functionalized for cell targets owing to their rich surface groups , , , , , , which is potential for selective delivery into the cells. On the other hand, similar to the strategy of activating prodrugs out of CB-5083 by natural enzymes, the large-size MEMs can easily realize space-controlled prodrug activation by implanting MEMs around the sick tissues and cells , , . Therefore, the target ability of enzyme-activated prodrug therapy (EAPT) can be significantly boosted. Third, the structures, sizes and shapes of MEMs can be finely tuned, so their catalytic property can be optimized for highly-efficient prodrug activation , , , . Fourth, the MEMs are easy to realize large-scale preparation. As a result, the cost can be much cheaper than natural enzymes for EAPT . To date, as alternatives to natural enzymes, MEMs have been explored for mimicking different types of natural enzymes, such as esterase , , , ribonuclease , , , , , , , , peroxidase , , , , etc. Therefore, the advancements and benefits of MEM family provide an opportunity for their potential or practical applications for EAPT.
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 , , , , , , , , 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 molecules 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 . 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.