Targeted Anti-Cancer Provascular Therapy Using Ultrasound, Microbubbles, and Nitrite to Increase Radiotherapy Efficacy
Bibliographic record
Abstract
Hypoxia is an important mechanism of resistance to radiation therapy in many human malignancies including prostate cancer. It has been recently shown that ultrasound targeted microbubble cavitation (UTMC) can increase blood perfusion in skeletal muscle by triggering nitric oxide signaling. Interestingly, this effect was amplified with a sodium nitrite coinjection. Since sodium nitrite has been shown to synergize with radiotherapy (RT), we hypothesized that UTMC with a sodium nitrite coinjection could further radiosensitize solid tumors by increasing blood perfusion and thus reduce tumor hypoxia. We evaluated (1) the ability of UTMC with and without nitrite to increase perfusion in muscle (mouse hindlimbs) and human prostate tumors using different pulse lengths and pressure; (2) the efficacy of this approach as a provascular therapy given directly before RT in the human prostate subcutaneous xenografts PC3 tumor model. Using long pulses with various pressures, in muscle, the provascular response following UTMC was strong (6.61 ± 4.41-fold increase in perfusion post-treatment). In tumors, long pulses caused an increase in perfusion (2.42 ± 1.38-fold) at lower mechanical index (MI = 0.25) but not at higher MI (0.375, 0.5, and 0.750) when compared to control (no UTMC). However, when combined with RT, UTMC with long pulses (MI = 0.25) did not improve tumor growth inhibition. With short pulses, in muscle, the provascular response following UTMC (SONOS) + nitrite was strong (13.74 ± 8.60-fold increase in perfusion post-treatment). In tumors, UTMC (SONOS) + nitrite also caused a provascular response (1.94 ± 1.20-fold increase in perfusion post-treatment) that lasted for at least 10 min, but not with nitrite alone. Interestingly, the blunted provascular response observed for long pulses at higher MI without nitrite was reversed with the addition of nitrite. UTMC (SONOS) with and without nitrite caused an increase in perfusion in tumors. The provascular response observed for UTMC (SONOS) + nitrite was confirmed by histology. Finally, there was an improved growth inhibition for the 8 Gy RT dose + nitrite + UTMC group vs 8 Gy RT + nitrite alone. This effect was not significant with mice treated by UTMC + nitrite and receiving doses of 0 or 2 Gy RT. In conclusion, UTMC + nitrite increased blood flow leading to an increased efficacy of higher doses of RT in our tumor model, warranting further study of this strategy.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".