Nanoscale CaO2 materials for synergistic transarterial chemoembolization in a VX2 orthotopic rabbit liver cancer model

Abstract

Transcatheter arterial chemoembolization (TACE) is extensively used in the treatment of hepatocellular carcinoma (HCC), but its efficacy is usually limited to secondary tumor hypoxia and other progressive exacerbation of the abnormal tumor microenvironment (TME). Herein, we synthesized polyvinyl pyrrolidone (PVP)-coated CaO₂ nanoparticles (CaO₂ NPs) and applied them as a synergistic agent to improve the antitumor efficacy of TACE. After injection into the tumor, CaO₂ NPs reacted with water to generate abundant oxygen, hydroxyl ions (OH^-), and calcium ions (Ca²⁺), thereby relieving tumor hypoxia, neutralizing acid, and overloading Ca²⁺ to mediate antitumor effects. Moreover, the effect of chemotherapeutic drugs within the TACE was improved due to the modulated TME. CaO₂ NPs efficiently regulated the TME and improved the antitumor effect of doxorubicin under hypoxia conditions in vitro. Compared to other groups, the TACE+CaO₂ NPs group achieved the lowest tumor growth rate, highest tumor necrosis rate, lowest expression of histological markers associated with hypoxia and angiogenesis (HIF-α, VEGF, and CD31), and highest CD8⁺ T cell recruitment in vivo. Thus, these findings demonstrated that CaO₂ NPs provide synergy for TACE therapy in the VX2 orthotopic rabbit liver cancer model, suggesting that they have a potential broad clinical application. STATEMENT OF SIGNIFICANCE: The efficacy of transcatheter arterial chemoembolization (TACE) for treatment of hepatocellular carcinoma is usually limited to secondary tumor hypoxia and other progressive exacerbation of the abnormal tumor microenvironment (TME). To address this issue, we synthesized CaO₂ nanoparticles (CaO₂ NP_S) which would react with water to generate abundant oxygen, hydroxyl ions (OH^-), and calcium ions (Ca²⁺), thereby relieving tumor hypoxia, neutralizing the acidic TME, and inducing Ca²⁺ overloading. The efficacy of CaO₂ NPs in combination with TACE was investigated in an orthotopic rabbit liver cancer model, and the results showed the great synergetic antitumor effect of TACE and CaO₂ NPs.

Keywords: Calcium peroxide; Hepatocellular carcinoma; Transcatheter arterial chemoembolization; Tumor microenvironment; VX2 tumor.