Porous Ca-HB-HA nanocomposites synergize with hyperbaric oxygen to boost targeted photodynamic therapy for hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is a primary liver cancer with high mortality. Developing therapeutic approaches with a low recurrence rate, systemic toxicity, or drug resistance is of paramount importance. This study investigates the impact of Ca-HB-HA-mediated photodynamic therapy (PDT) on HCC cells and the synergistic effects of hyperbaric oxygen (HBO) therapy. This study developed Ca-HB-HA nanoparticles, which were comprehensively characterized through DLS, zeta potential, FTIR, and BET analyses to confirm their hydrodynamic diameter, surface charge, chemical composition, and porous structure. The Ca-HB-HA nanoparticles significantly enhanced reactive oxygen species (ROS) generation in H22 cells and modulated pH under PDT. In the HCC xenograft model, Ca-HB-HA-mediated PDT combined with HBO exhibited synergistic antitumor efficacy, confirmed by in vivo imaging, apoptosis assays, and histopathological analysis. This study successfully developed Ca-HB-HA loaded with photosensitizer HB. Systematic characterization confirmed their suitable hydrodynamic size, surface charge, and porous structure, along with favorable drug encapsulation and loading capacity. H22 cells exhibited the highest uptake of Ca-HB-HA nanocomposites at 4 h. As an efficient photosensitizer in H22 cells, Ca-HB-HA can generate ROS and increase the pH value in the tumor microenvironment upon light activation. HBO therapy synergistically enhanced H22 cell toxicity and restored the low apoptosis rate induced by hypoxic conditions. In the HCC xenograft model, HBO combined with Ca-HB-HA-mediated PDT significantly inhibited tumor growth, which was supported by TUNEL staining results. Biochemical index detection of blood samples showed that this therapeutic approach caused no hepatorenal or cardiac toxicity, which was further confirmed by HE staining. Additionally, small animal imaging confirmed the precise tumor targeting of the Ca-HB-HA. This study found that Ca-HB-HA-mediated PDT can increase the pH and ROS levels in the tumor microenvironment, while combined HBO therapy enhances H22 cell apoptosis mediated by cleaved PARP (c-PARP) and cleaved caspase-3 (c-Caspase3), inhibits tumor growth, and causes minimal cellular and hepatorenal damage during this process.