Drug-Eluting Porous Embolic Microspheres For Trans-Arterial Delivery Of Dual Synergistic Anti-Cancer Therapy For The Treatment Of Liver Cancer.

Blockage of blood supply while administering chemotherapy to tumors, using Trans-arterial chemoembolization (TACE), is the most common treatment for intermediate and advanced-stage unresectable Hepatocellular carcinoma (HCC). However, HCC is characterized by a poor prognosis and high recurrence rates (∼30%), partly due to a hypoxic pro-angiogenic and pro-cancerous microenvironment. This paper investigates how modifying tissue stress while improving drug exposure in target organs may maximize the therapeutic outcomes. Porous degradable polymeric microspheres (MS) were designed to obtain a gradual occlusion of the hepatic artery that nourishes the liver, while enabling efficient drug perfusion to the tumor site. The fabricated porous MS were introduced intrahepatically and designed to release a combination therapy of Doxorubicin (DOX) and Tirapazamine (TPZ), which is a hypoxia-activated prodrug. Liver cancer cell lines that were treated with the combination therapy under hypoxia revealed a synergic anti-proliferation effect. An orthotopic liver cancer model, based on N1-S1 hepatoma in rats, was used for the efficacy, biodistribution, and safety studies. Porous DOX-TPZ MS were very effective in suppressing tumor growth in rats, and induction tissue necrosis was associated with high intra-tumor drug concentrations. Porous particles without drugs showed some advantages over non-porous particles, suggesting that morphology may affect the treatment outcomes. This article is protected by copyright. All rights reserved.