Split Enzyme Reassembly (SER) Platforms
In a split enzyme reassembly (SER) platform, an enzyme is split into inactive or “off” fragments and fused to targeting moieties, i.e., peptide and/or protein partners. In the absence of target, the split enzyme fragments do not reassemble and enzyme activity is not observed. However, if the targeting moieties find their target, the interaction brings the split enzyme fragments into close proximity. Those fragments associate and/or fold and a functional enzyme is generated and the enzyme is then “on.” Common split enzymes, including beta-galactosidase (beta-gal), beta-lactamase, and luciferase to name a few, can be used as reporters for molecular imaging of cellular dynamics or directed enzyme pro-drug activators for chemotherapy. Beta-gal can be utilized to activate a pro-drug therapy in a two-step approach. In the first step, a drug-activating enzyme is targeted or expressed in tumors. In the second step, a nontoxic pro-drug, a substrate of the exogenous enzyme that is now localized to tumor tissues, is administered systemically. The result is that a systemically administered pro-drug can be converted to high local concentration of an active anti-cancer drug in tumors by a targeted enzyme, such as beta-gal. Several pro-drug substrates exist, which, when activated, generate toxicity for cancer cells both in vitro and in vivo.