Intracellular Activation of Anticancer Therapeutics Using Polymeric Bioorthogonal Nanocatalysts

Abstract

Bioorthogonal catalysis provides a promising strategy for imaging and therapeutic applications, providing controlled in situ activation of pro‐dyes and prodrugs. In this work, the use of a polymeric scaffold to encapsulate transition metal catalysts (TMCs), generating bioorthogonal “polyzymes,” is presented. These polyzymes enhance the stability of TMCs, protecting the catalytic centers from deactivation in biological media. The therapeutic potential of these polyzymes is demonstrated by the transformation of a nontoxic prodrug to an anticancer drug (mitoxantrone), leading to the cancer cell death in vitro.

Transition Metal Scaffolds Used To Bring New‐to‐Nature Reactions into Biological Systems

“…Following polymer formation via ROMP, hydrophobic pockets will be formed to allow the collection of transition metal complexes. In literature, this approach has been utilized to construct catalytically active polyzymes embedded with either ruthenium, [288] or iron-based complexes. [289] Given that nature routinely utilizes lipid-based compartmentalization (e. g., exosomes, organelles, cells, etc), encapsulating catalytic metals within a biocompatible shell for its protection represents a logical approach for adaptation into biological systems.…”

“…Following polymer formation via ROMP, hydrophobic pockets will be formed to allow the collection of transition metal complexes. In literature, this approach has been utilized to construct catalytically active polyzymes embedded with either ruthenium, [288] or iron‐based complexes [289] …”

Degradable ZnS-Supported Bioorthogonal Nanozymes with Enhanced Catalytic Activity for Intracellular Activation of Therapeutics

“…Bioorthogonal chemistry uses abiotic chemical reactions as tools for biological and biomedical applications. − Bioorthogonal catalysis via transition-metal catalysts (TMCs) provides in situ continuous generation of imaging and therapeutic agents using transformations that cannot be accomplished by natural enzymes. − However, the direct use of “naked” TMCs faces difficulties including poor water solubility, low stability, and lack of biocompatibility. , In particular, TMCs are generally very sensitive to the presence of serum proteins, limiting their utility in biological and biomedical applications. , Incorporating TMCs into nanomaterials provides bioorthogonal “nanozymes” that feature enhanced solubility, stability, and biocompatibility. − The resulting nanozymes can activate therapeutics and imaging agents in situ from inactive precursors, providing on-demand “drug factories” for therapeutic applications including anticancer, − antimicrobial, , and anti-inflammatory treatments …”

Tools and Methods for Investigating Synthetic Metal-Catalyzed Reactions in Living Cells

“…The advantages of synthetic metal catalysts are that they are cell permeable, synthetically tunable, and easily produced on gram scales or larger. The first demonstration of using metal catalysts to promote intracellular reactions was reported in 1985, and since then, an increasing number of reports have appeared in the literature. − To date, metal catalysts have been used to carry out diverse intracellular reactions, including azide–alkyne cycloaddition, − amide coupling, azide reduction, , C–C bond cross-coupling, , olefin metathesis, protecting group cleavage, − ring formation, , and transfer hydrogenation , (Scheme ). Although these examples are remarkable, they represent only a small percentage of what synthetic catalysts are capable of achieving .…”