Ultrasonic tornado for precision medicine Improving tumor microenvironment through oxygen-loaded microbubbles trapping by acoustic vortex tweezer

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2020-07-29 | Department of Engineerings and Technologies, MOST | Source

Chemotherapy is one of the treatment options for cancer patients, the chemo-drug was delivered into tumor via systemic blood circulation. But in fact, this drug delivery route is inefficiency and unsafe. This is because the continuously circulating blood flow prevents the drug from remaining in the tumor area, and also brings the drug into the healthy tissue. These drawbacks of circulation-delivered drug method will potentially be addressed by a novel precision medicine technique, acoustic vortex tweezer (AVT), which is developed by Professor Chih-Kuang Yeh from the Department of Biomedical Engineering and Environmental Sciences of National Tsing Hua University. After injecting special oxygen-loaded microbubbles (O2-MBs), the O2-MBs circulating in the blood flow can be gathered by AVT and oxygenate the tumor cells. In the future, AVT is expected to capture drugs and develop into a clinical application model of precision medicine.

Professor Yeh noticed that the lack of oxygen inside the tumor greatly decreases the outcome of chemical and radiotherapy treatments. The reason for tumor hypoxia is that most of the tumor vessels are abnormal and dysfunctional vessels, which restrict transport oxygen and nutrients into tumor. Therefore, if oxygen can be accurately delivered into the tumor, it will change the morphology and function of tumor blood vessels, enhance the ability of tumor blood vessels to transport oxygen and drugs, or increase sensitivity to radiotherapy, and even activating anti-tumor immune cells.

How to accurately deliver oxygen to the tumor? In fact, Professor Yeh has been in the business for a long time and developed two key technologies including (1) AVT trapping particles; (2) ultrasonic contrast agent microbubbles, and intends to develop into precision medicine applications. Under the Ministry of Science and Technology subsidized research project, a new concept "Acoustic vortex tweezers" was proposed in 2010. Later, a study on "Combing with acoustic vortex tweezers with ultrasonic contrast microbubbles" was published at an international conference, using MBs as a drug carrier, and combined with AVT for delivering the drug to the target area. On the other hand, the team developed a phospholipid MB as an oxygen carrier, and proved that it can reduce tumor hypoxia. This technology has been patented by the Taiwan. In order to further increase the concentration of O2-MBs within the tumor, the Professor Yeh’s team proposed a research project entitled "O2-MBs combined with AVT to improve the tumor microenvironment", using the AVT technology to gather circulating O2-MBs and control release oxygen into tumor.

The research team stated that this method is to precisely control the distribution of O2-MBs within the body through a non-invasive method, which will help for the inefficiency transport of tumor abnormal vascular. It will accumulate a large number of O2-MBs in the tumor area and trigger oxygen release to alleviate tumor hypoxia. In the future, AVT can even be used to control the spatial distribution of drugs, so that a large number of drugs can be concentrated at the lesion without contacting normal healthy tissues, achieving precise drug delivery. In the next stage, the research team will develop AVT with clinical 2D array ultrasound transducer system and be integrated with the ultrafast ultrasonic plane-wave imaging for real-time monitoring O2-MBs trapping, accumulation and release oxygen within tumors. It is hoped that in the future, it can enter clinical trials for tumor treatment, establishing a new type of precision medical application strategy.

Professor Yeh specializes in ultrasound biomolecular diagnosis, treatment, and drug delivery research. His research and innovation breakthrough lie in the development of ultrasound-responsible agents for ultrasound imaging and drug delivery: (1) ultrasonic imaging agent development (drug/gene carrier), including MBs, acoustic phase change droplets, and superhydrophobic acoustic-sensitive nanoparticles; (2) establishment of ultrasound imaging system and the development of algorithms. (3) Application and integration of experimental models from external cells and animals. The team’s latest research is using AVT to manipulate particles for non-invasive drug manipulation and precise drug release applications. The tornado-liked acoustic field transmitted by an array transducer can trap particles at a potential well through the pressure gradients, which can solve the problems of acoustic attenuation and complicated structure in high-frequency and standing-wave tweezers. Notably, the technique patents of AVT were published in USA and EU. Professor Yeh hopes to use AVT with O2-MBs as a non-invasive manner to regulate the tumor microenvironment, and then initiate a series of anti-tumor routes, such as tumor vascular normalization, immune activation, and metastasis inhibition. In the future, the possibility of using AVT to control the spatial distribution of drugs within the body to improve the safety and efficacy of medication will be explored.

Professor Yeh’s research team has translate the laboratory MBs research into clinical application. In January 2013, a few graduates established TRUST Bio-sonics, with a capital of 6 million, and has completed the fourth capital increase in Hsinchu Science Park. Professor Yeh served as the company’s consultant to assist the company’s small-scale mass production and patent layout. The product has been tested for tumor ablation procedure in the hospital, and completed myocardial perfusion imaging, toxicology, animal safety tests, formulation stability, process verification, etc. It has been cooperating with pharmaceutical companies to produce and conduct GLP preclinical safety trials since 2015, and formally obtained the US FDA human clinical trial approval in 2018. The research team of Professor Yeh hopes to use the AVT as a non-invasive manner to manipulate spatial distribution of O2-MBs in body for regulating tumor microenvironment. In the future, it is expected to be applied to cancer tumor treatment in clinical trials, and establish a set of accurate ultrasound diagnosis and treatment platform based on O2-MBs therapy. The team expects to convert the above research results into patents, introduce the technology into commercialization, and plan to establish a new medical material company in 2020.


[1] Y. J. Ho, S. W. Chu, E. C. Liao, C. H. Fan, H. L. Chan, K. C. Wei, and C. K. Yeh*, "Normalization of Tumor Vasculature by Oxygen Microbubbles with Ultrasound," Theranostics, vol. 9, no. 24, pp. 7370-7383, 2019.
[2] S. T. Kang and C. K. Yeh*, "Potential-Well Model in Acoustic Tweezers," IEEE Transactions on Ultrasonics, Ferroelectrics, and Frequency Control, vol. 57, no. 6, pp. 1451–1459, 2010.
[3] W. C. Lo, C. K. Yeh, "Precise collection of microbubbles by acoustic vortex under flow conditions," IEEE Ultrasonics Symposium, 2018. (October 22-25, Kobe, Japan)
[4] W. C. Lo, S. T. Kang, and C. K. Yeh, “Two-Dimensional Microbubble Collection in an Acoustic Vortex,” IEEE EMBC Conference, 2015. (August 25-29, Milan, Italy)

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