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摘要
Purpose: Ultrasound-induced mild hyperthermia has advantages for noninvasive, localized and controlled drug delivery. In this study, a tissue-mimicking agarose-based phantom with a thermally sensitive indicator was developed for studying the spatial drug delivery profile using ultrasound-induced mild hyperthermia. Methods: Agarose powder, regular evaporated milk, Dulbecco's phosphate-buffered saline (DPBS), n-propanol, and silicon carbide powder were homogeneously mixed with low temperature sensitive liposomes (LTSLs) loaded with a self-quenched near-infrared (NIR) fluorescent dye. A dual-mode linear array ultrasound transducer was used for insonation at 1.54 MHz with a total acoustic power and acoustic pressure of 2.0 W and 1.5 MPa, respectively. After insonation, the dye release pattern in the phantom was quantified based on optical images, and the three-dimensional release profile was reconstructed and analyzed. A finite-difference time-domain-based algorithm was developed to simulate both the temperature distribution and spatial dye diffusion as a function of time. Finally, the simulated dye diffusion patterns were compared to experimental measurements. Results: Self-quenching of the fluorescent dye in DPBS was substantial at a concentration of 6.25 x 10(-2) mM or greater. The transition temperature of LTSLs in the phantom was 35 degrees C, and the release reached 90% at 37 degrees C. The simulated temperature for hyperthermia correlated with the thermocouple measurements with a mean error between 0.03 +/- 0.01 and 0.06 +/- 0.02 degrees C. The R-2 value between the experimental and simulated spatial extent of the dye diffusion, defined by the half-peak level in the elevation, lateral and depth directions, was 0.99 (slope = 1.08), 0.95 (slope = 0.99), and 0.80 (slope = 1.04), respectively, indicating the experimental and simulated dye release profiles were similar. Conclusions: The combination of LTSLs encapsulating a fluorescent dye and an optically transparent phantom is useful for visualizing and modeling drug release in vitro following ultrasound-induced mild hyperthermia. The coupled temperature simulation and dye-diffusion simulation tools were validated with the experimental system and can be used to optimize the thermal dose and spatial and temporal dye release pattern.
- 出版日期2013-8
