Biodegradable Poly(dodecane succinate-ran-caprolactone) nanoparticles with isodimorphic behavior for sustained release of CPT-11 in triple negative breast cancer

Engineering semicrystalline microstructures 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 unitcell parameters. These structural differences directly governed nanoparticle formation, drug affinity, and colloidal stability. All copolymers yielded spherical nanoparticles (~100–150 nm) via a sustainable acetonebased nanoprecipitation method. However, only the low-crystallinity, PCL-rich composition (DS11CL89) 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 pHdependent 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.