Polyacrylic acid nanoparticles encapsulating doxorubicin: structural analysis and encapsulation mechanism

Abstract

Monodisperse poly(acrylic acid) (PAA) nanoparticles were synthesized via precipitation polymerization. Markedly high loading of the anticancer drug doxorubicin hydrochloride (DOX) was achieved, with drug contents reaching approximately 44 wt%, which exceeds the values typically reported for polymer-based nanocarriers. Structural analyses using transmission electron microscopy and small-angle X-ray scattering (SAXS) revealed that the encapsulated DOX was not distributed uniformly but instead formed a distinct core-localized DOX-rich domain while maintaining the spherical morphology of the PAA nanoparticles. Notably, each PAA nanoparticle typically contained a single DOX-rich domain, and morphologies with multiple domains were rarely observed, indicating a single-domain nucleation and growth mechanism. Quantitative single-particle fluorescence analysis further demonstrated that the proportion of DOX-loaded particles increased systematically with increasing drug loading, reaching 75.8% at 44 wt%, which was consistent with the results of the SAXS analysis. In addition, the PAA nanoparticles exhibited strong and stable affinity toward hydroxyapatite, underscoring their potential for bone-targeted drug delivery. Collectively, these findings establish PAA nanoparticles as robust, high-capacity carriers with unique structural features and bone affinity, offering a promising platform for advanced drug delivery systems, particularly in the treatment of metastatic cancers. Monodisperse poly(acrylic acid) nanoparticles encapsulate doxorubicin at high contents (~44 wt%), forming a single core-localized DOX-rich domain as revealed by SAXS and TEM while retaining spherical morphology. Single-particle fluorescence showed that the fraction of DOX-positive particles increased with loading, reaching 75.8% at 44 wt% DOX. The particles also exhibit strong hydroxyapatite affinity, highlighting their promise as robust, high-capacity carriers for bone-targeted drug delivery and potential treatment of metastatic cancers.