CaCO3‐Encapuslated Microspheres for Enhanced Transhepatic Arterial Embolization Treatment of Hepatocellular Carcinoma

Abstract Transcatheter arterial embolization (TAE) is an extensively applied treatment method for hepatocellular carcinoma (HCC). However, the worsened tumor microenvironment (TME, e.g., reduced pH post‐TAE) may result in unsatisfactory therapeutic outcome. Herein, a new kind of embolic agent, calcium carbonate encapsulated alginate microspheres (CaCO 3 ‐ALG MSs) are synthesized. Such CaCO 3 ‐ALG MSs are able to neutralize the tumor pH owing to the reaction of CaCO 3 with protons, which would not affect the overall morphology of microspheres after decomposition of CaCO 3 . TAE treatment with CaCO 3 ‐ALG MSs is then conducted in an orthotopic rat liver cancer model. 18 F‐Fluorodeoxyglucose micropositron emission tomography/computed tomography imaging is conducted post‐TAE and discovered that intra‐arterial injection of CaCO 3 ‐ALG MSs shows obvious enhanced therapeutic outcome compared to the same treatment with bare ALG MSs or the clinically used lipiodol. Further studies including analysis of immune cells in tumors, cytokine assays, and bioinformatics analysis all verify the reverse of immunosuppressive TME toward a more immunosupportive one after TAE with CaCO 3 ‐ALG MSs. The research not only presents a new CaCO 3 ‐containing embolic agent for enhanced TAE treatment of HCC but also highlights a clinically meaningful approach to improve cancer treatment via tumor pH neutralization.