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

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

  • Acad Radiol. 2025 Jul;32(7):4121-4133. doi: 10.1016/j.acra.2025.03.034.
Tingting Luo 1,  Lei Yao 2,  You Wu 1,  Yi Zhang 3,  Lian Lu 4,  Peng He 5,  Ningshan Li 1,  Xiaoxiao Dong 1,  Zheng Liu 6
Affiliations

Affiliations

  • 1 Department of Ultrasound, Xinqiao Hospital, Army Medical University, Chongqing, China (T.L., Y.W., L.L., P.H., N.L., X.D., Z.L.).
  • 2 Department of Ultrasound, Army 75th Group Military Hospital, Dali, Yunnan, China (L.Y.).
  • 3 Department of Ultrasound, the Seventh Medical Center of Chinese PLA General Hospital, Beijing, China (Y.Z.).
  • 4 Department of Ultrasound, Xinqiao Hospital, Army Medical University, Chongqing, China (T.L., Y.W., L.L., P.H., N.L., X.D., Z.L.); Department of Ultrasound, the 900th Hospital of the PLA Joint Logistic Support Force, Fuzhou, Fujian, China (L.L.).
  • 5 Department of Ultrasound, Xinqiao Hospital, Army Medical University, Chongqing, China (T.L., Y.W., L.L., P.H., N.L., X.D., Z.L.); Department of Ultrasound, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan, China (P.H.).
  • 6 Department of Ultrasound, Xinqiao Hospital, Army Medical University, Chongqing, China (T.L., Y.W., L.L., P.H., N.L., X.D., Z.L.). Electronic address: liuzheng@tmmu.edu.cn.
PMID: 40234163 DOI: 10.1016/j.acra.2025.03.034
Abstract

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.

Keywords

Diagnostic ultrasound; Microbubble; Nitric oxide; Tumor hypoxia; Ultrasound imaging.

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