聚焦式超音波搭配超音波顯影劑影響巨分子在生物組織傳輸特性之探討

Investigation of Macromolecular Transport Variation in Tissues for Focused Ultrasound Sonication in the Presence of Microbubbles

呂國維(Kuo-Wei Lu)

指導教授 ： 林文澧

國立臺灣大學/工學院/醫學工程學研究所/碩士(2009年)

https://doi.org/10.6342/NTU.2009.10663

摘要

巨分子藥物載體可以標定腫瘤進行專一性治療，且有較長的血液半衰期，是現今腫瘤藥物主要發展的對象之一，但因為腫瘤組織本身特性的限制，使得巨分子藥物載體無法進入腫瘤組織內部，要克服此問題，除了從藥物的改良著手外，改變腫瘤組織的特性也是一個方法。前人研究指出聚焦式超音波搭配超音波顯影劑可使微血管壁破裂，特定參數的使用已經證明可讓藥物在活體中遞送達到更好的效果。
本研究主要探討聚焦式超音波搭配顯影劑造成血管通透性及血管外擴散係數的改變。我們使用螢光葡萄聚糖當作巨分子藥物載體，並以雙光子顯微技術活體且動態觀察螢光葡萄聚糖在小鼠皮膚組織的分布情形。超音波的頻率為1MHz，最大負聲壓0.6MPa，重覆頻率為1Hz，爆發長度10ms，顯影劑劑量為200 μL/kg。
由實驗結果得知，超音波搭配顯影劑可破壞正常組織的血管壁，並造成巨分子從血管中滲出。並藉由Nakamura等人在1974年所建立的分子運輸模型與本研究來做數據分析，計算出施打超音波之後巨分子在組織的運輸參數，並進一步由文獻探討得知，超音波搭配超音波顯影劑會造成巨分子在血管外的擴散係數增加。此種研究方法可用於研究超音波搭配顯影劑對於腫瘤組織的影響，並提供腫瘤治療的策略。

關鍵字

聚焦式超音波 ； 超音波顯影劑 ； 雙光子顯微術 ； 血管 ； 運輸參數

並列摘要

Macromolecular drug carrier is one of the major research subjects in anti-cancer drug development today due to its long half-life and specific targeting ability. However, its penetration ability into the tumor tissue is constrained by the tumor’s microenvironments. To improve the anti-cancer drug distribution in the tumor tissue, we can modify the drug’s functions and characteristics or change the tumor’s vascular properties and microenvironments. It has been shown that focused ultrasound with microbubbles could disrupt the vascular wall and the use of specific parameters could enhance the drug delivery. In this study, we investigated the permeability variation of blood vessels into tissue for focused ultrasound sonication in the presence of microbubbles (ultrasound contrast agent). We used dextran rhodamine as micromolecular drug carrier and used two-photon microscope to observe the permeation of dextran from the blood vessels into the tissue of normal mouse. The focused ultrasound used is 1.0 MHz driving frequency, 0.6 MPa peak negative pressure, 1 Hz repetition frequency, and 10 ms burst, and the ultrasound contrast agent dose was 200 μL/kg injected into the mouse tail vein. The experimental results showed that focused ultrasound with microbubbles can effectively disrupt the blood vessel walls of normal mouse tissue and cause the extravasation of macromolecules. We used a mathematical model with diffusion (Nakamura et al.,1974) to calculate and analyze the transport parameters of macromolecules during ultrasound sonication. We found that the diffusion coefficient of macromolecules during sonication was greater than that published in literatures. The methods used in this study can further be employed to investigate the transport characteristics of tumor blood vessels and the dose distribution in tumor tissue for focused ultrasound with microbubbles, and the results may provide useful information for future cancer treatment strategy.

並列關鍵字

Focused ultrasound ； Ultrasound contrast agent ； Two-photon microscope ； Blood vessels ； Transport parameters

參考文獻

[19] 黃啟訓(2008)。聚焦式超音波配合超音波顯影劑應用於小鼠正常與腫瘤血管滲透性之探討。碩士論文，國立台灣大學醫學工程研究所。

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