雷射與超音波同步誘發穴蝕效應輔助聲穿孔術之研究

Synchronized optically and acoustically induced cavitation for sonoporation

黃思翰(Sy-Han Huang)

指導教授 ： 李百祺

國立臺灣大學/電機資訊學院/生醫電子與資訊學研究所/碩士(2017年)

https://doi.org/10.6342/NTU201704170

摘要

微氣泡超音波對比劑除了能提高影像對比度外也能用來作為藥物釋放的載體，透過超音波誘發微氣泡產生穴蝕效應所製造的聲穿孔效應能有效的將藥物送入目標處。但其應用於腫瘤細胞時的藥物輸送效率受限於微氣泡的大小以及在血液循環時不穩定等要素影響使得奈米液滴態藥物載體逐漸興起。然而奈米液滴需先汽化成微氣泡才能被誘發穴蝕效應，而現階段不論是聲學激發相變液滴汽化法或是光學激發相變液滴汽化法所使用的超音波能量和雷射能量皆對於人體組織有安全上的疑慮，因此本研究提出同時使用雷射與超音波來降低液滴汽化與穴蝕效應閾值。本研究使用1MHz超音波探頭與808nm脈衝雷射來激發實驗室自製的金奈米液滴，藉由於超音波最負聲壓處同步施加脈衝雷射的方式使金奈米液滴汽化並誘發出穴蝕效應來達成聲穿孔效果來提升藥物釋放效率。研究中使用慣性穴蝕效應劑量來量化穴蝕效應，並比較了不同超音波最負聲壓與雷射光通量在聲壓時序變化上對於穴蝕效應的影響。當以慣性穴蝕效應為縱軸，雷射相對超音波施放的延遲時間為橫軸，可以觀察到，慣性穴蝕效應的變化與聲壓變化一致，於最負聲壓下同步施加雷射最容易誘發出穴蝕效應，而此時所使用的超音波負聲壓為-526.1kPa，光通量為12.02mJ/cm2。與先前研究相比，使用連續波雷射搭配超音波應用於光熱治療時，當使用的超音波負聲壓為-526kPa時所需的雷射能量為2W/cm2 並持續5分鐘，顯見使用脈衝雷射並於超音波最負聲壓時施放能大幅降低雷射的能量使用。而將此技術應用於光熱治療中時，除了能降低雷射光通量的使用外，因為使用脈衝雷射緣故，可以透過奈米金桿與金奈米液滴所產生的汽化現象與光聲效應來進行光聲影像以便觀察組織內的金粒子分布來提高光熱治療之效率與安全性。

關鍵字

聲學激發相變液滴汽化 ； 光學激發相變液滴汽化法 ； 穴蝕效應 ； 聲穿孔術 ； 光熱治療 ； 光聲影像

並列摘要

Microbubble-based ultrasound contrast agents not only can improve image quality but also can serve as drug-delivery vehicles. The sonoporation effect produced by ultrasound-assisted cavitation can effectively enhance the delivery of encapsulated nanoparticles to the target site. However, the delivery efficiency is often limited due to their inability to extravasate and instability in the blood stream. An alternative is to use nanodroplets to replace microbubbles, but the droplets need to be vaporized first before inducing cavitation. The vaporization can be induced either acoustically or optically, in both cases a high energy is required which may raise safety concerns. Thus, it is the main goal of this research to propose and investigate methods for reduced vaporization thresholds with gold nanodroplets by irradiating laser pulses at the rarefaction phase of the acoustic wave. A 1MHz ultrasound transducer and a pulsed wave laser (808nm) were used. By synchronizing the laser pulse and the negative peak pressure of ultrasound, the experimental results indicate that cavitation can be more effectively induced. To quantify the cavitation effect, differential inertial cavitation dose (dICD) is used. It is found that the dICD value changed with the relative timing between the laser pulse and the acoustic wave. Results show that at -526.1kPa negative peak pressure, the laser with a fluence at 12.02mJ/cm2 can successfully induce cavitation. Compared with previous research, where a continuous wave laser was used, a laser intensity of 2W/cm2 for 5 minutes was needed. It is demonstrated that the proposed method can significantly lower the laser exposure energy while effectively inducing the cavitation effect. Also, since a pulsed laser is used, the thermal expansion and vaporization signal from gold nanodroplets can also be used for photoacoustic imaging as a means to monitor the distribution of gold nanoparticles and to facilitate photothermal therapy.

並列關鍵字

acoustic droplets vaporization ； optical droplets vaporization ； cavitation ； sonoporation ； photothermal therapy ； photoacoustic imaging

參考文獻

1. McGuire, S., World Cancer Report 2014. Geneva, Switzerland: World Health Organization, International Agency for Research on Cancer, WHO Press, 2015. Adv Nutr, 2016. 7(2): p. 418-9.

2. Knudson, A.G., Jr., Mutation and cancer: statistical study of retinoblastoma. Proc Natl Acad Sci U S A, 1971. 68(4): p. 820-3.

3. Fisher, B., et al., Twenty-year follow-up of a randomized trial comparing total mastectomy, lumpectomy, and lumpectomy plus irradiation for the treatment of invasive breast cancer. N Engl J Med, 2002. 347(16): p. 1233-41.

4. Sekine, I., et al., A literature review of molecular markers predictive of clinical response to cytotoxic chemotherapy in patients with breast cancer. Int J Clin Oncol, 2009. 14(2): p. 112-9.

5. Wang, Y.H., et al., Photoacoustic/ultrasound dual-modality contrast agent and its application to thermotherapy. J Biomed Opt, 2012. 17(4): p. 045001.