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  • To provide a brief critical evaluation


    To provide a brief critical evaluation of this technology and an outlook, we note that performance of SMEPT is critically dependent on each of the components making up this platform, namely the substrate, the enzyme, and the prodrug. With regards to the latter, SMEPT is built on the experience and success of the previously developed technique, namely ADEPT, which dictated the choice of glucuronide prodrugs for implementation of this methodology to localized drug synthesis. Indeed, glucuronide derivatives are typically devoid of physiological activity and typical toxicity of these agents is 100–1000 lower (in terms of IC50) compared to the parent toxin masked within the prodrug [60], [61]. This spells a high degree of site-specific mode of drug delivery achieved through minimal non-specific, off-site activity of the administered prodrug. However, the main disadvantage of glucuronides is their short plasma half-life [62] (from minutes to few hours). One highly promising development in this field is the recent introduction of albumin-bound glucuronide prodrugs [63]. Albumin is the most abundant protein in human plasma and at the same time is among the most successful tools of drug delivery [64], [65], [66], [67]. This protein has a phenomenal blood residence time of 3weeks in humans, a capacity achieved through physiological mechanism of albumin recycling [68]. Albumin-bound glucuronide prodrugs revealed highly promising EPT-based bioconversion profile and an overall successful EPT in vivo[63]. It is likely that SMEPT and other modes of EPT will benefit tremendously from this and possibly other designs of prodrugs with long blood residence time. From a different perspective, a major step forward taken by SMEPT lies in the use of endogenous prodrugs, that is natural molecules, as substrates for EPT [52]. This aspect may significantly facilitate translational success of SMEPT. Further aid in translational progress may come from engineering SMEPT into the well-developed implantable biomaterials. As it stands, existing examples of SMEPT have hardly explored the BAMB-4 mg of biomaterials used as implants. We anticipate that engineering EPT is potentially a fruitful avenue of research with such examples of biomaterials as electrospun fibers [69], injectable (in situ gelling) hydrogels [70], and post-operative tissue sealants [71]. The highly admirable achievement of SMEPT with regards to the choice of the enzyme is that this mode of EPT, unlike all other enzyme-prodrug therapies, already makes use of enzyme mimics. Indeed, the field of artificial enzymes is hot with developments being highly warranted by diverse sub-disciplines of applied and fundamental science, from industrial catalysis [72] to enzyme engineering [73], [74] and cell mimicry [75], [76]. Artificial enzymes are poised to be more stable than their natural counterpart, are potentially less immunogenic, and may perform reactions that are un-natural, using prodrugs with no physiological activity. Enzymatic activity can be engineered using inorganic nanoparticles [77], [78] protein scaffolds, [73], [74], macromolecular and supramolecular scaffolds [79] and hydrogels [80] – in the latter case making up macroscopic implantable biomaterials with inherent biocatalytic activity. We anticipate that the field of enzyme mimicry will have a strong impact on subsequent development of SMEPT. With regards to translational development of SMEPT, we acknowledge that we are not aware of any trials currently underway to validate this methodology in clinical settings. It appears fair to say that enthusiasm and commitment from corporate developers does not match that of academic partners. One reason for a dampened interest of corporate partners in SMEPT (revealed to us in private communication) is the envisioned hurdles of regulatory approval. Specifically, for success of SMEPT, approval is needed for the biocatalytic implant and also for the administered prodrug, effectively presenting a “double trouble” approval prospect. However, we hope that this review would spur broader, well-deserved interest in SMEPT, specifically in light of most recent developments in the field. Good example is the successful design of implantable biomaterials for localized synthesis of nitric oxide, which effectively creates a niche for such products and their associated unique functionality. Acceptance of SMEPT may be further facilitated by the use endogenous compounds as prodrugs, as was already achieved for generation of nitric oxide using natural RSNO [52], [55].