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Enzymatic Non-Covalent Synthesis of a Versatile Platform for Bioorthogonal Prodrugs Activation to Combat Drug Resistance
preprintsubmitted on 29.10.2020, 05:13 and posted on 30.10.2020, 08:22 by Qingxin Yao, Shuo Gao, Chengling Wu, Ting Lin, Yuan Gao
Multidrug resistance (MDR) often leads to the failure of the anticancer treatment. Besides the blockage of those MDR pathways, the development of more potent drugs are of urgent needs but largely postponed due to imbalance between safety and efficacy. The prodrug strategy, especially with bioorthogonal activation has shown immerse potential to balance safety and efficacy, while recent studies focus on few drug entities such as doxorubicin and MMAE, leaving the vast collection of toxins undetermined. Here we have enumerated typical molecular entities ranging from FDA approved drugs (doxorubicin, paclitaxel) to a heated ADC warhead (MMAF-OMe) and a trichothecene toxin (Mytoxin A) to demonstrate that the trans-cyclooctene (TCO) caging may serve as a general prodrug design to increase the therapeutic index for bioactive molecules. These prodrugs can be efficiently activated on-demand by the bioorthogonal activators whose distribution is regulated by the cell specific enzymatic non-covalent synthesis of supramolecular self-assemblies. These cell-specific prodrugs activation could not only reduce the toxicology of drugs but also enhance the synergistic therapeutic effect within a broad range of dose ratio. More importantly, these prodrugs activation share the same activator bearing assemblies, which allows the flexible shift of drug identities to successfully combat MDR cancer in vivo. In general, this versatile bioorthogonal prodrug activation platform is readily applicable to enlarge the therapeutic window for various bioactive molecules. We envision that the spatiotemporal controlled prodrug activation should facilitate the drug discovery and development.