Reactivity of Pseudozyma antarctica lipase B towards the synthesis of end-capped polycaprolactone for drug delivery

State-of-the-art delivery systems currently rely on chemical synthesis routes for drug encapsulation. However, these methods have inherent drawbacks concerning toxicity, selectivity, and the potential for burst release. To overcome these limitations, the enzymatic synthesis of polymer-drug conjugates emerges as a promising alternative to promote eco-friendliness and safety in production and grants precise control over the resulting structures. In this study, we delved into the reactivity of Pseudozyma ( Candida ) antarctica lipase B for polyesters’ capping with small molecules. For that purpose, Quantum Mechanics/Molecular Mechanics simulations were used to predict the conjugation reactions. These predictions were translated to the laboratory, where the enzymatic reactions were replicated, subsequently benchmarking them against metal oxide-catalysed reactions. The outcome of our experiments was the successful generation of end-capped oligo/polycaprolactone, with their molecular weights spanning from 540 to 2600 g mol −1 with an enzymatic approach, and slightly higher when applying conventional catalysis, and with isolation yields up to 68.4 %. This work underscores the potential of enzyme-driven strategies in fabricating precisely engineered drug delivery systems, marking a significant stride toward more efficient and controlled therapeutics synthesis. • C alB was tested for ROP and conjugation reactions and benchmarked against a metal catalyst. • Molecular weights, isolation yields, and incorporation rates of up to 3200 g mol −1 , 68.4 % and 86 %, respectively. • The end-capped PCL products showed good thermal stability and melting points, suggesting application in drug delivery.