Highly Tumor-Specific and Long-Acting Iodine-131 Microbeads for Enhanced Treatment of Hepatocellular Carcinoma with Low-Dose Radio-Chemoembolization

Transarterial radioembolization (TARE) is considered the standard treatment for intermediate-stage hepatocellular carcinoma (HCC). Iodine-131 (¹³¹I)-labeled lipiodol TARE is an effective treatment for HCC but has been withdrawn due to its poor retention in tumor lesions and significant distribution in normal tissues with severe side effects. In this work, a highly tumor-specific ¹³¹I-TARE agent with long-time retention is developed by simply introducing tyrosine to poly(vinyl alcohol) (PVA) drug-eluting microbeads (Tyr-PVA-DEBs). The labeling efficiency of ¹³¹I-labeled microbeads remains above 85% in 50% serum for 31 days. Micro-single-photon emission computed tomography/computed tomography (μSPECT/CT) evidences that the ¹³¹I-labeled microbeads accumulate in the orthotopic N1S1 hepatoma of rats for 31 days following intra-arterial injection. The cumulative radiation dose per cubic centimeter of the tumor is at least 13 678-fold higher than that of normal tissues. The highly tumor-selective radiation of the ¹³¹I-labeled microbeads allows localized delivery of 345.04 ± 139.16 Gy to the tumor following a single injection dose as low as 0.2 mCi of ¹³¹I. Moreover, the ¹³¹I-labeled microbeads are loaded with doxorubicin hydrochloride (DOX) through the carboxy groups on tyrosine of the polymer. The ¹³¹I-DOX-loaded microbeads present a synergetic antitumor effect without recurrence in comparison with the microbeads labeled with ¹³¹I or loading DOX alone, attributed to the sensitization of DOX to ¹³¹I-induced ionizing radiation damage to DNA under the embolization-induced hypoxia. Our results demonstrate a high tumor retention of ¹³¹I-labeled embolic agent for low-dose transarterial radio-chemoembolization (TARCE) with a synergetic therapeutic effect on treating HCC, showing potential for clinical application.