• Isodimorphic DS–CL copolymers enable tunable crystalline microstructures. • Composition controls crystallinity and lamellar thickness. • Copolymer microstructure dictates nanoparticle formation and drug affinity. • PCL-rich DS 11 CL 89 leads to stable irinotecan-loaded nanoparticles. • Nanoparticles show sustained drug release and anticancer activity. Engineering semicrystalline microstructure in biodegradable polymers offers a powerful yet underexplored strategy to regulate drug–matrix interactions and pharmaceutical performance. Here, we report isodimorphic poly(dodecane succinate- ran -caprolactone) (DS–CL) random copolymers as structurally tunable platforms for nanoparticle-mediated delivery of CPT-11 in triple-negative breast cancer (TNBC). Differential scanning calorimetry and synchrotron wide-angle X-ray scattering revealed composition-dependent pseudoeutectic behavior, demonstrating that subtle variations in comonomer content modulate thermal properties, crystallinity, and unit-cell parameters. These structural differences directly governed nanoparticle formation, drug affinity, and colloidal stability. All copolymers yielded spherical nanoparticles (∼100–150 nm) via a sustainable acetone-based nanoprecipitation method. However, only the low-crystallinity, PCL-rich composition (DS 11 CL 89 ) enabled stable CPT-11 encapsulation, underscoring the decisive role of the PCL-type crystalline phase in drug–polymer interactions. Drug-loaded nanoparticles exhibited sustained release (∼50% at 24 h) with pH-dependent kinetics and enhanced surface charge stability. Whereas unloaded nanoparticles were cytocompatible in normal breast epithelial cells, with negligible toxic effects in cancer cells, CPT-11-loaded formulations induced dose-dependent cytotoxicity selectively in MDA-MB-231 TNBC cells with reduced acute toxicity compared to free drug, consistent with controlled intracellular release. This study establishes a direct structure–property–function relationship in isodimorphic random copolyesters, positioning crystalline microstructure engineering as a rational design principle for precision nanomedicine targeting aggressive breast cancer subtypes.
Cillari et al. (2026) studied this question.