Probing enzyme access to polymeric systems is of interest due to the novel potential for optimization of these platforms’ compatibility and utility with in situ biological factors. Here we report the incorporation of a caspase-cleavable linker into convergent, theranostic bottlebrush (BP) and brush-arm star polymers (BASPs) synthesized via ring-opening metathesis polymerization (ROMP), that enable coumarin release and subsequent turn-on fluorescent signal only upon cellular apoptosis. 7-amino-4-methylcoumarin (AMC) was utilized as a reporter that was statically quenched while bound to the polymeric substrate, and that turned on upon enzymatic cleavage by apoptotic effector protein caspase-3. Varied polymeric architectures in terms of backbone length (DP) and crosslinking degree were evaluated for cleavage access by fluorescence output kinetics. In vitro studies validated the efficacy of these substrates as fluorescent turn-on systems triggered by delivery and subsequent activity of an antineoplastic agent. Kinetic studies elucidated the increased access of the 17 kDa active form of the enzyme to BP tails indicated by the higher fluorescence output of shorter DP substrates. This work provides first steps toward cataloging the design criteria required for polymer-based theranostics via a novel, electronics-based evaluation metric catered to interact with in vivo factors, while laying the groundwork for a theranostic approach toward cancer therapy and imaging. Subsequent studies will use this platform in vitro and in vivo to validate the imaging and therapeutic potential of these new constructs and its translational utility.

Caspase-cleavable fluorescent turn-on bottlebrush-based polymers enable elucidation of architectural effects on interactions with biological factors and evaluation of drug efficacy in biological systems

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ACS Fall 2022

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.