A Hydrogel for Nitric Oxide Sensitization Chemotherapy Mediated by Tumor Microenvironment Changes in 3D Spheroids and Breast Tumor Models

Background: Nitric oxide (NO) is a low-toxicity and high-efficiency anticancer treatment that can augment the cytotoxicity of doxorubicin (DOX) towards breast cancer cells, thereby exhibiting a favorable effect on chemotherapy sensitization. Objective: The study aimed to establish a hydrogel that sensitizes chemotherapy by inducing local inflammatory stimulation to change the tumor microenvironment and promote NO production. The purpose of the study was to examine the anti-tumor effect in vivo and in vitro. Methods: The functional properties of the composite hydrogels were tested by UV spectrophotometry and NO detection kit. CCK8, DCFH-DA fluorescent probe, Calcein-AM/PI detection kit, and confocal detection methods were used for the cytocompatibility and cytotoxicity of the composite hydrogels. The subcutaneous tumor volume, weight, and tumor inhibition rate of 4T1 breast cancer cells were evaluated for pharmacodynamic study in vivo. Results: Each component of hydrogel has good biocompatibility. The combination of gas therapy and chemotherapy can significantly enhance the effect of inhibiting tumor cell growth. The tumor growth of tumor- bearing mice in the hydrogel administration group was slow, and the tumor inhibition rate was 85.10%. The body weight grew steadily, and no significant pathological changes were observed in the H&E staining of major organs. result: Each component of hydrogel has good biocompatibility. The combination of gas therapy and chemotherapy can significantly enhance the effect of inhibiting tumor cell growth. The tumor growth of tumor-bearing mice in hydrogel administration group was slow, and the tumor inhibition rate was 85.10%. The body weight grew steadily, and no significant pathological changes were observed in H&E staining of major organs. Conclusion: A composite hydrogel with alginate as the carrier was successfully established, which was based on improving the tumor microenvironment to trigger gas therapy combined with chemotherapy for tumor treatment.