科技部新聞稿
超音波龍捲風腫瘤診斷與精準醫療
帶氧微氣泡結合漩渦式聲鉗改善腫瘤微環境
日期：109年7月29日
發稿單位：工程技術研究發展司
聯絡人：張哲浩副研究員
電話：2737-7371
E-mail：thchang@nstc.gov.tw
行政院近年來推動生醫產業創新，強調跨域科技結合生技醫藥，透過精準的理念提升效率以及強化安全，為發展利基精準醫學，科技部補助清華大學醫環系葉秩光教授，研發出漩渦式超音波聲鉗技術，注射特製的帶氧微氣泡後，可將血液中流動的帶氧微氣泡捕捉並聚集在腫瘤位置，使腫瘤細胞充氧，未來可望捕捉藥物，發展為精準醫療臨床應用模式。
化學藥物治療是癌症患者的治療選項之一，藥物藉由全身血液循環流入腫瘤部位殺死腫瘤細胞。但由於不斷循環的血液會使藥物無法停留在腫瘤區域，也會將藥物帶入健康組織，這種藥物輸送模式的治療效率低也不安全。
葉秩光教授注意到腫瘤內部一旦缺氧，會大幅影響化學與放射治療的治療成效，而促使腫瘤缺氧的原因是腫瘤內大多是功能缺陷的不成熟血管，運輸氧氣及養分的能力較差。因此若能精準將氧氣遞送至腫瘤內部，將可改善腫瘤血管的型態及功能，提升腫瘤血管輸送氧氣與藥物的能力，或是增加對放射治療的敏感度，甚至誘發後續抗腫瘤免疫細胞的活化，能多方面提升腫瘤治療效果。
但是該怎麼將氧氣準確輸送至腫瘤？葉秩光教授其實早已布局許久，研發出超音波聲鉗操控微粒與超音波對比劑微氣泡兩大技術，打算發展為精準醫療應用。在科技部補助研究計畫下，從最早2010年提出一種新型概念「漩渦式聲鉗」；之後於國際會議發表「漩渦式聲鉗結合超音波對比劑微氣泡」之研究，利用微氣泡搭載藥物作為藥物載體，並搭配漩渦式聲鉗對微氣泡產生強烈的聲輻射力做操控，能有益於藥物精準遞送至目標區域。另一方面，團隊發展出磷脂質微氣泡載體，可以把氧氣穩定包覆，並證實能透過改善腫瘤微環境的氧合作用途徑，降低腫瘤缺氧問題，此技術已獲中華民國專利。而為了進一步增加帶氧微氣泡在腫瘤的累積量，團隊提出「帶氧微氣泡結合漩渦式聲鉗改善腫瘤微環境」之研究計畫，利用漩渦式聲鉗技術先蒐集血液中流動的帶氧微氣泡，再精準操控聚集在腫瘤位置並釋放氧氣。
研究團隊表示這項方法是透過非侵入方式精準操控生物體內帶氧微氣泡的分佈，將可以彌補腫瘤血管運輸效率低下的缺陷，先於腫瘤區域大量累積帶氧微氣泡，再驅動微氣泡釋放氧氣以緩解腫瘤缺氧問題，未來甚至可用來操控藥物的分佈位置，使藥物可以大量集中在病灶處而不接觸到正常組織，達到精準醫療藥物遞送。下一階段，研究團隊將以漩渦式聲鉗為基礎，擴增至現行醫療診斷使用的二維陣列探頭，利用超快速平面波成像技術，以特殊串接波型的方式擊破帶氧微氣泡，達到即時監控帶氧微氣泡在腫瘤中被捕捉並釋放氧氣的過程。希望將來可進入臨床試驗並實際運用於癌症腫瘤治療中，建立一套以帶氧微氣泡治療為基礎的超音波診斷與治療平台，提供一種新型的精準醫療應用模式。
葉教授專研於超音波生物分子診斷與治療以及超音波於藥物輸送與釋放研究，其研究創新突破在於載藥/基因微氣泡顯影劑與奈米材料應用於超音波成像與藥物傳遞/釋放的實現，研究成果的質與量均相當豐碩。其研究的創新與突破包括三個層次，(1)超音波顯影劑開發(藥物/基因載體)，包含微氣泡、聲學相變微滴與超疏水聲敏奈米粒子。(2)超音波顯影劑成像系統建立與演算法開發。(3)從外細胞、動物實驗模型應用與整合。團隊最新研究為漩渦式聲鉗操控微粒之能力用於非侵入式操控藥物與精準釋放藥物的應用。漩渦式聲鉗突破傳統聲鉗無法應用於人體的限制，以陣列式探頭發射出如龍捲風結構的超音波聲場，利用龍捲風於中心處的位能梯度差，形成向中心捕捉的作用力來捕捉粒子，相關技術已獲得美國、歐盟專利。葉教授希望利用漩渦式聲鉗以非侵入方式操控帶氧微氣泡改善腫瘤微環境，進而啟動一系列腫瘤治療途徑，例如誘發腫瘤血管正常化、抗腫瘤免疫活化及抑制腫瘤轉移等。未來也將嘗試利用漩渦式聲鉗操控體內藥物分布，從精準醫療的角度提升用藥安全及效能。
葉教授研究團隊已將實驗室超音波顯影劑研究實際成果推廣於臨床醫學上使用，在2013年1月由數名畢業生成立博信生物科技，資本額600萬，目前完成第四次增資進駐竹北生醫園區，葉教授擔任該公司顧問協助公司產品小型量產與專利佈局等，產品階段已於醫院實際腫瘤燒灼程序下進行協助造影的測試，並完成心肌灌注造影、毒理、安全性動物試驗、配方穩定度、製程驗證等工作，2015 年起即與藥廠合作生產並進行 GLP 臨床前安全性試驗，並於2018年正式取得美國FDA人體臨床試驗許可。而葉教授研究團隊希望利用本計畫之漩渦式聲鉗以非侵入方式在生物體內操控帶氧微氣泡的優勢，用以改善腫瘤微環境，未來可望進行臨床試驗並實際運用於癌症腫瘤治療中。並建立一套以帶氧微氣泡治療為基礎的精準超音波診斷治療平台，實現醫用超音波診斷與治療一體化。團隊預計將上述之研究成果轉化成專利，把技術導入商業化，並規劃2020年成立醫材新創公司。未來4年科技部將跨部會推動精準健康戰略產業，布局下世代精準健康產業發展藍圖，達成產業創新翻轉並實現2030全齡精準健康之未來願景。
〈參考資料〉
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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.
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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.
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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)
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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)
研究成果聯絡人
葉秩光
科技部傑出研究獎、國家生策會國家新創獎
國立清華大學生醫工程與環境科學系 特聘教授
300 新竹市光復路二段101號
E-mail：ckyeh@mx.nthu.edu.tw
Tel：03-5715131#34240
Press Release
July 29, 2020
Ultrasonic tornado for precision medicine
Improving tumor microenvironment through oxygen-loaded microbubbles trapping by acoustic vortex tweezer
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.
Reference
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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.
-
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.
-
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)
-
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)
Media Contact
Prof. Chih-Kuang Yeh
Department of Biomedical Engineering and Environmental Sciences, National Tsing Hua University, Taiwan
Tel: +886-3-5715131#34240
E-mail: ckyeh@mx.nthu.edu.tw
