Porous PLGA microspheres with recruited ions and doxorubicin for triple-combination therapy of larger hepatocellular carcinoma

Easy recurrence of large hepatocellular carcinoma (HCC) after microwave (MW) ablation or transarterial chemoembolization (TACE) is still very challenging. In this study, porous polylactide-co-glycolide (PLGA) microspheres as a MW-susceptible TACE agent (P-PLGA@DN microspheres) for triple-combination therapy of large HCC were developed via the double emulsion technique using recruited ions (Na⁺ and Cl^-) and doxorubicin hydrochloride (DOX·HCl) to enhance the efficiency of MW absorption and DOX chemotherapy after tumor embolization. The as-prepared microspheres with superior MW-heat conversion can enlarge the ablation area by >53% in a simulated physiological environment. The in vivo efficiencies of chemotherapy and thermal therapy for ICR mice bearing H22 tumor cells under the assistance of P-PLGA@DN microspheres reach to 100%. In the experiments of synergistic therapy combining TACE with MW ablation on VX2 tumor-bearing New Zealand white rabbits, PLGA@DN microspheres can increase ablation area by more than 50%, enhancing the necrosis of tumor cells and effectively inhibiting tumor growth. These results demonstrate that the potential application of P-PLGA@DN microspheres in synergistic therapy of large HCC can be envisioned.