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Normalization of Tumor Vasculature by Oxygen Microbubbles with Ultrasound
Yi-Ju Ho1, Shu-Wei Chu1, En-Chi Liao2
1Department of Biomedical Engineering and Environmental Sciences, National Tsing Hua University, Hsinchu, Taiwan.
Abstract:
Tumor microenvironment influences the efficacy of anti-cancer therapies. The dysfunctional tumor vasculature limits the efficiency of oxygenation and drug delivery to reduce treatment outcome. A concept of tumor vascular normalization (VN), which inhibits angiogenesis to improve vessel maturity, blood perfusion, and oxygenation, has been demonstrated under the anti-angiogenic therapy. The efficiency of drug delivery and penetration is increased by enhancing perfusion and reducing interstitial fluid pressure during the time window of VN. However, anti-angiogenic agents only induce transient VN and then prune vessels to aggravate tumor hypoxia. To repair tumor vessels without altering vessel density, we proposed to induce tumor VN by local oxygen release via oxygen microbubbles with ultrasound. With tumor perfusion enhancement under ultrasound contrast imaging tracing, the time window of VN was defined as 2-8 days after a single oxygen microbubble treatment. The enhanced tumor oxygenation after oxygen microbubble treatment inhibited hypoxia inducible factor-1 alpha (HIF-1α)/vascular endothelial growth factor (VEGF) pathway to improve the morphology and function of tumor vasculature. The pericyte coverage and Hoechst penetration of tumor vessels increased without any changes to the vessel density. Finally, the intratumoral accumulation of anti-cancer drug doxorubicin could be increased 3-4 folds during tumor VN. These findings demonstrate that regulating tumor oxygenation by oxygen microbubbles could normalize dysfunctional vessels to enhance vascular maturity, blood perfusion, and drug penetration. Furthermore, ultrasound perfusion imaging provides a simple and non-invasive way to detect the VN time window, which increases the feasibility of VN in clinical cancer applications.
Insights
Local oxygen release using oxygen microbubbles and ultrasound normalizes tumor vasculature, enhancing drug delivery. This approach improves tumor oxygenation and vessel function without altering vessel density, offering a new strategy for cancer therapy.
Area of Science:
- Oncology
- Biomedical Engineering
- Nanotechnology
Background:
- Tumor microenvironment and vasculature critically impact anti-cancer therapy efficacy.
- Dysfunctional tumor vasculature impairs oxygenation and drug delivery, reducing treatment outcomes.
- Current anti-angiogenic therapies offer transient vascular normalization (VN) and can worsen hypoxia.
Purpose of the Study:
- To investigate tumor vascular normalization (VN) induced by local oxygen release via oxygen microbubbles and ultrasound.
- To define the therapeutic time window for VN using ultrasound perfusion imaging.
- To evaluate the impact of oxygen microbubble treatment on tumor oxygenation, vascular morphology, and drug penetration.
Main Methods:
- Induction of VN by local oxygen release using oxygen microbubbles activated by ultrasound.
- Ultrasound contrast imaging to trace tumor perfusion and define the VN time window (2-8 days post-treatment).
- Assessment of tumor oxygenation, hypoxia-inducible factor-1 alpha (HIF-1α)/vascular endothelial growth factor (VEGF) pathway, pericyte coverage, and drug (doxorubicin) penetration.
Main Results:
- Oxygen microbubble treatment enhanced tumor oxygenation and normalized vasculature without changing vessel density.
- Improved pericyte coverage and increased Hoechst dye penetration into tumor vessels were observed.
- Intratumoral accumulation of doxorubicin increased 3-4 fold during the VN time window.
- Ultrasound perfusion imaging effectively detected the VN time window.
Conclusions:
- Regulating tumor oxygenation with oxygen microbubbles normalizes dysfunctional vessels, enhancing vascular maturity, perfusion, and drug penetration.
- This ultrasound-guided approach provides a non-invasive method to detect the VN window, increasing clinical applicability.
- Oxygen microbubbles represent a promising strategy to improve anti-cancer drug delivery and therapeutic outcomes.
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