Poly(ε-caprolactone) nanoparticles for irinotecan delivery synthesized via enzymatic ring-opening polymerization in organic solvents, ionic liquids, and bulk conditions

Effective drug delivery remains a major challenge in the treatment of colorectal cancer, particularly due to poor drug stability and non-selective cytotoxicity. This study addresses these limitations by developing poly(ε-caprolactone) (PCL)-based nanoparticles (NPs) for the delivery of irinotecan (CPT-11), a chemotherapeutic agent with recognized clinical relevance. The PCL matrices were synthesized via enzymatic ring-opening polymerization (eROP), catalyzed by Candida antarctica lipase B, and conducted in two molecular liquids – toluene and 1-butyl-3-methylimidazolium hexafluorophosphate (an ionic liquid) – as well as under bulk (solvent-free) polymerization conditions. This enzymatic approach enables the preparation of biodegradable carriers under mild conditions, which may offer advantages for biomedical applications such as drug delivery. We demonstrate that the choice of reaction medium strongly influences polymerization efficiency and the performance of the resulting NPs. The PCL-based NPs had mean diameters ranging from 334 to 426 nm and exhibited satisfactory colloidal stability. CPT-11 was released in a sustained manner without an initial burst, following the Weibull model with an excellent fit (R 2 ≈ 0.99). The release mechanism was primarily governed by Fickian diffusion and Case II transport, resembling first-order kinetics, as indicated by a Weibull shape parameter (b ~1.0). Release profiles varied with both pH and NPs composition. Importantly, the PCL-based NPs significantly enhanced the cytotoxicity of CPT-11 against HCT-116 colorectal cancer cells in a time- and concentration-dependent manner, particularly under mildly acidic conditions (pH 6.5). These findings underscore the potential of PCL-based NPs as effective and selective carriers for irinotecan delivery, especially in acidic tumor microenvironments. • Poly(ε-caprolactone) (PCL) matrices were synthesized via enzymatic ring-opening polymerization (eROP) in toluene or ionic liquid (BMIM PF₆) as medium, and the bulk method, for irinotecan delivery. • BMIM PF₆ create a unique microenvironment that favors cyclization mechanisms over linear polymerization of PCL. • Polymerization medium during PCL synthesis significantly influenced nanoparticle characteristics and drug release behavior. • Irinotecan-loaded PCL nanoparticles exhibited sustained release governed by Fickian diffusion and Case II transport. • Enhanced cytotoxicity of NPs against HCT-116 cells was observed, particularly under mildly acidic conditions (pH 6.5).