Procaine and Doxorubicin Coloaded Microspheres for Painless and Potent Transarterial Chemoembolization

Transarterial chemoembolization (TACE) is the standard treatment for intermediate-stage hepatocellular carcinoma (HCC). However, its clinical efficacy is severely limited by postembolization syndrome (PES) and the physical vascular barrier induced by embolization. To address these limitations, we developed multifunctional polyvinyl alcohol embolization microspheres modified with polydopamine and coloaded with procaine (PCA) and doxorubicin (DOX), termed pDA-PVA/PCA-DOX. MD/MM-PBSA simulations and physicochemical characterization confirmed that the pDA coating enabled efficient coloading of both drugs via hydrogen bonding and π-π stacking, with the particle size meeting clinical requirements for TACE. The loading capacities of PCA and DOX in this codelivery system reached 4.6 and 4.8 times those of commercial microspheres, respectively. The adsorption kinetics fitted a pseudo-second-order model, and the microspheres exhibited distinct pH-responsive release behavior. In vitro and in vivo studies demonstrated that the sustained release of PCA downregulated proinflammatory cytokines, upregulated IL-10 expression, and reduced macrophage infiltration, thereby exerting analgesic and anti-inflammatory effects. Furthermore, the codelivery of PCA and DOX exerted synergistic antitumor efficacy with a coefficient of drug interaction (CDI) of 0.62-0.63, significantly inhibiting the proliferation, migration, and invasion of HCC cells. In mouse subcutaneous xenograft and rabbit VX2 liver tumor TACE models, the pDA-PVA/PCA-DOX significantly suppressed tumor growth, downregulated angiogenesis-related markers including VEGF, EGFR, and CD31, and modulated the immune microenvironment by increasing intratumoral infiltration of CD4+ and CD8+ T cells. Additionally, the pDA-PVA/PCA-DOX exhibited favorable biocompatibility and hemocompatibility, causing no persistent hepatic or renal toxicity post-TACE. Collectively, this multifunctional coloaded microsphere system integrates efficient embolization, anti-inflammation, analgesia, synergistic chemotherapy, and microenvironment modulation, providing experimental evidence for optimizing TACE therapeutic strategies.