Coarse‐Grained Simulations Rationalize Thermosensitivity and Hydrolytic Degradation of Vinyl Copolymers Obtained by Radical Ring‐Opening Polymerization

ABSTRACT Thermosensitive vinyl polymers with an upper critical solution temperature (UCST) have gained particular attention in drug delivery applications. However, since the UCST is strongly influenced by various parameters (e.g., copolymer composition, molar mass, concentration, and presence of salt), exploring the full range of possibilities to develop effective polymer‐based nanocarriers with precisely controlled UCST properties adapted to each biomedical application is very challenging. These developments, generally based on trial‐and‐error strategies, require extremely time‐ and resource‐consuming experiments. In addition, vinyl copolymers are not degradable, which may hinder their clinical application. Recently, well‐defined vinyl copolymers combining both degradability and thermosensitivity properties have been obtained by copolymerizing acrylamide (AAm) and 5,6‐benzo‐2‐methylene‐1,3‐dioxepane (BMDO) as cyclic ketene acetals (CKA) comonomer, via radical ring‐opening polymerization (rROP), leading to much faster degradation under physiological conditions than previously‐developed CKA‐containing copolymers and even aliphatic polyesters. Nevertheless, such an unprecedented step forward in the field of rROP was left unexplained. Herein, we employed coarse‐grained (CG) molecular dynamics (MD) simulations to investigate the thermosensitive behavior and degradability of CKA‐containing vinyl copolymers. Our simulations successfully: (i) reproduced the UCST behavior and transition temperature ( T c ) value of P(AAm‐ co ‐BMDO) copolymers and (ii) revealed that local solvation environments and supramolecular organizations (e.g., aggregation state and steric hindrance) could drastically alter the accessibility of ester groups in P(AAm‐ co ‐BMDO), P(MMA‐ co ‐BMDO), and P(OEGMA‐ co ‐BMDO) copolymers, ultimately rationalizing their experimentally observed degradability under physiological conditions. This approach provides insight at the molecular level into the origin of the thermosensitive and degradable behaviors of CKA‐containing vinyl copolymers and provides a predictive framework for the design of biodegradable polymer materials for biomedical applications.