Ultrasound-Stimulated Microbubbles Cavitation Combined with Nitric Oxide Signaling Pathway to Alleviate Tumor Hypoperfusion and Hypoxia in MC38 Tumor Model

Rationale and Objectives Ultrasound-stimulated microbubbles cavitation (USMC) has been proved to improve tumor blood perfusion, which is closely related to the rise in nitric oxide (NO) bioavailability. This study was aimed to investigate whether the co-administration of USMC and NO signaling molecule could contribute to a further enhancement of tumor perfusion. Materials and Methods Ninety-six MC38 tumor-bearing mice were divided into eight groups to compare the efficacy of different NO-related molecules alone and in combination with USMC, including L -arginine ( L -Arg), NOC-18 and sodium nitrite (SN). To better evaluate the changes of tumor perfusion, six mice in each group received contrast-enhanced ultrasound imaging and the other six received ultra-resolution microscopy before and after treatment. Differences in NO generation and tumor hypoxia after treatments were also compared to identify an ideal co-therapy strategy. Further, inhibitors of NO synthase and NO receptor were adopted to explore mechanisms of the co-therapy in improving tumor perfusion. Results Contrast-enhanced ultrasound imaging and ultra-resolution microscopy showed that USMC and SN had a positive synergistic effect in improving tumor perfusion. NO synthase inhibitor failed to block this effect while NO receptor inhibitor did. The tumor perfusion enhancement accompanied with the alleviation of tumor hypoxia and the increase of NO production. L -Arg and NOC-18 did not demonstrate synergistic effects with USMC. Conclusion Co-administration of USMC and NO pathway is a promising modality to alleviate tumor hypoperfusion and hypoxia, among which SN is an effective reagent playing a positive synergistic effect with USMC.