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Nanodroplet-Vaporization-Assisted Sonoporation for Highly Effective Delivery of Photothermal Treatment.

Liu WW, Liu SW, Liou YR, Wu YH, Yang YC, Wang CR, Li PC - Sci Rep (2016)

Bottom Line: This study used nanodroplets to significantly enhance the effectiveness of sonoporation relative to using conventional microbubbles.Enhanced cavitation also leads to significant enhancement of the sonoporation effects.Our in vivo results show that nanodroplet-vaporization-assisted sonoporation can increase the treatment temperature by more than 10 °C above that achieved by microbubble-based sonoporation.

View Article: PubMed Central - PubMed

Affiliation: National Taiwan University, Graduate Institute of Biomedical Electronics and Bioinformatics, Taipei 106, Taiwan.

ABSTRACT
Sonoporation refers to the use of ultrasound and acoustic cavitation to temporarily enhance the permeability of cellular membranes so as to enhance the delivery efficiency of therapeutic agents into cells. Microbubble-based ultrasound contrast agents are often used to facilitate these cavitation effects. This study used nanodroplets to significantly enhance the effectiveness of sonoporation relative to using conventional microbubbles. Significant enhancements were demonstrated both in vitro and in vivo by using gold nanorods encapsulated in nanodroplets for implementing plasmonic photothermal therapy. Combined excitation by ultrasound and laser radiation is used to trigger the gold nanodroplets to induce a liquid-to-gas phase change, which induces cavitation effects that are three-to-fivefold stronger than when using conventional microbubbles. Enhanced cavitation also leads to significant enhancement of the sonoporation effects. Our in vivo results show that nanodroplet-vaporization-assisted sonoporation can increase the treatment temperature by more than 10 °C above that achieved by microbubble-based sonoporation.

No MeSH data available.


Related in: MedlinePlus

AuNDs-assisted PPTT in vivo.(a) Schematic of the procedure for applying AuNDs-assisted PPTT to tumor-bearing mice. (b) The use of a holding device to ensure that the laser and two ultrasound transducers were co-focused, followed by the same electrical system setup, meant that dICD could be measured in vivo. Upon exposure to ultrasound and laser radiation simultaneously for 2.5 minutes, the dICD value was enhanced by 3.1 fold for AuNDs compared to AuMBs with the same treatment, and it was enhanced by 4.2 fold compared to AuNDs exposed to ultrasound only. The enhancement increased to around 10 fold even when the dICD value of the AuNDs with dual energy application has gradually decreased during the last 2.5 minutes. The time zero (t = 0) labeled at the X axis is the starting time to transmit the ultrasound signal from the 1 MHz transmitting transducer, and the amount of cavitation signals are collected by the 10 MHz receiving transducer with a13-seconds delayed. (c) Frames from the infrared thermal imaging. (d) Real-time temperature recording of the treated tumors during contrast-agent-assisted PPTT. The dotted line indicates the time when exposed to the laser radiation was stopped.
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f6: AuNDs-assisted PPTT in vivo.(a) Schematic of the procedure for applying AuNDs-assisted PPTT to tumor-bearing mice. (b) The use of a holding device to ensure that the laser and two ultrasound transducers were co-focused, followed by the same electrical system setup, meant that dICD could be measured in vivo. Upon exposure to ultrasound and laser radiation simultaneously for 2.5 minutes, the dICD value was enhanced by 3.1 fold for AuNDs compared to AuMBs with the same treatment, and it was enhanced by 4.2 fold compared to AuNDs exposed to ultrasound only. The enhancement increased to around 10 fold even when the dICD value of the AuNDs with dual energy application has gradually decreased during the last 2.5 minutes. The time zero (t = 0) labeled at the X axis is the starting time to transmit the ultrasound signal from the 1 MHz transmitting transducer, and the amount of cavitation signals are collected by the 10 MHz receiving transducer with a13-seconds delayed. (c) Frames from the infrared thermal imaging. (d) Real-time temperature recording of the treated tumors during contrast-agent-assisted PPTT. The dotted line indicates the time when exposed to the laser radiation was stopped.

Mentions: To further understand the therapeutic efficiency in vivo, we designed a holding device that allowed an ultrasound transmitter, ultrasound receiver, and laser probe to be co-focused on the targeted tumor site. A schematic of the in vivo application method is shown in Fig. 6a. Briefly, after intratumorally injecting AuNRs-encapsulated contrast agent via a needle, the holding device with the instruments set up as described above was placed over the target tumor for applying treatment and for measuring the cavitation signals. The treatment was applied for 5 minutes each time, and this was repeated every 3 days for a total treatment course of 12 days. This setup allowed the cavitation signals to be successfully received from the subcutaneously stimulated implanted liver tumor. The received broadband signals were further analyzed using the same method described in Fig. 4a. Consistent with the in vitro results shown in Fig. 4a, the in vivo dICD value of AuNDs exposed to ultrasound and laser radiation simultaneously also gradually increased as time passed, while it decreased with time when AuNDs were exposed to ultrasound only or AuMBs were exposed to ultrasound and laser radiation simultaneously. Similarly, the dICD value of laser-exposed AuNDs remained difficult to calculate (Fig. 6b). To examine the thermal effects induced by AuNDs-assisted PPTT, infrared thermal imaging and a thermocouple were applied to measure the temperature of the contrast-agent-treated tumor during the therapy. For infrared thermal imaging, NDs, AuNDs, and AuMBs were individually injected into one side of implanted tumors followed by exposure to ultrasound and laser radiation simultaneously for 5 minutes, during which infrared thermal images were obtained every minute. The results showed that the temperature elevation during the exposure was greatest for AuNDs-treated tumors, with the temperature reaching over 50 °C after 5 minutes of stimulation (Fig. 6c). In contrast, the temperatures measured in NDs- and AuMBs-treated tumors were only elevated to around 35 °C and 42 °C, respectively. Since infrared thermal imaging can only measure the surface temperature, we inserted a thermocouple into the tumor beneath the treatment site to record the intratumor temperature achieved during the treatment. Consistent with the results of infrared thermal imaging, treatment with AuNDs followed by exposure to ultrasound and laser radiation simultaneously could effectively and rapidly elevate the tumor temperature to over 50 °C. Moreover, treatment with either NDs or AuMBs followed by the same excitation method could not elevate the tumor temperature as effectively as when using AuNDs. Together these data indicate that the thermal effect of photothermal therapy was successfully enhanced by applying AuNDs to the tumor followed by exposure to ultrasound and laser radiation simultaneously. Under such treatment, the temperature was sufficiently elevated to cause irreversible thermal damage to the tumor and thus increase the probability of enhancing the photothermal therapeutic efficiency. The enhancement of both the cavitation and thermal effects suggests that enhanced sonoporation is also possible in in vivo treatment.


Nanodroplet-Vaporization-Assisted Sonoporation for Highly Effective Delivery of Photothermal Treatment.

Liu WW, Liu SW, Liou YR, Wu YH, Yang YC, Wang CR, Li PC - Sci Rep (2016)

AuNDs-assisted PPTT in vivo.(a) Schematic of the procedure for applying AuNDs-assisted PPTT to tumor-bearing mice. (b) The use of a holding device to ensure that the laser and two ultrasound transducers were co-focused, followed by the same electrical system setup, meant that dICD could be measured in vivo. Upon exposure to ultrasound and laser radiation simultaneously for 2.5 minutes, the dICD value was enhanced by 3.1 fold for AuNDs compared to AuMBs with the same treatment, and it was enhanced by 4.2 fold compared to AuNDs exposed to ultrasound only. The enhancement increased to around 10 fold even when the dICD value of the AuNDs with dual energy application has gradually decreased during the last 2.5 minutes. The time zero (t = 0) labeled at the X axis is the starting time to transmit the ultrasound signal from the 1 MHz transmitting transducer, and the amount of cavitation signals are collected by the 10 MHz receiving transducer with a13-seconds delayed. (c) Frames from the infrared thermal imaging. (d) Real-time temperature recording of the treated tumors during contrast-agent-assisted PPTT. The dotted line indicates the time when exposed to the laser radiation was stopped.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4837361&req=5

f6: AuNDs-assisted PPTT in vivo.(a) Schematic of the procedure for applying AuNDs-assisted PPTT to tumor-bearing mice. (b) The use of a holding device to ensure that the laser and two ultrasound transducers were co-focused, followed by the same electrical system setup, meant that dICD could be measured in vivo. Upon exposure to ultrasound and laser radiation simultaneously for 2.5 minutes, the dICD value was enhanced by 3.1 fold for AuNDs compared to AuMBs with the same treatment, and it was enhanced by 4.2 fold compared to AuNDs exposed to ultrasound only. The enhancement increased to around 10 fold even when the dICD value of the AuNDs with dual energy application has gradually decreased during the last 2.5 minutes. The time zero (t = 0) labeled at the X axis is the starting time to transmit the ultrasound signal from the 1 MHz transmitting transducer, and the amount of cavitation signals are collected by the 10 MHz receiving transducer with a13-seconds delayed. (c) Frames from the infrared thermal imaging. (d) Real-time temperature recording of the treated tumors during contrast-agent-assisted PPTT. The dotted line indicates the time when exposed to the laser radiation was stopped.
Mentions: To further understand the therapeutic efficiency in vivo, we designed a holding device that allowed an ultrasound transmitter, ultrasound receiver, and laser probe to be co-focused on the targeted tumor site. A schematic of the in vivo application method is shown in Fig. 6a. Briefly, after intratumorally injecting AuNRs-encapsulated contrast agent via a needle, the holding device with the instruments set up as described above was placed over the target tumor for applying treatment and for measuring the cavitation signals. The treatment was applied for 5 minutes each time, and this was repeated every 3 days for a total treatment course of 12 days. This setup allowed the cavitation signals to be successfully received from the subcutaneously stimulated implanted liver tumor. The received broadband signals were further analyzed using the same method described in Fig. 4a. Consistent with the in vitro results shown in Fig. 4a, the in vivo dICD value of AuNDs exposed to ultrasound and laser radiation simultaneously also gradually increased as time passed, while it decreased with time when AuNDs were exposed to ultrasound only or AuMBs were exposed to ultrasound and laser radiation simultaneously. Similarly, the dICD value of laser-exposed AuNDs remained difficult to calculate (Fig. 6b). To examine the thermal effects induced by AuNDs-assisted PPTT, infrared thermal imaging and a thermocouple were applied to measure the temperature of the contrast-agent-treated tumor during the therapy. For infrared thermal imaging, NDs, AuNDs, and AuMBs were individually injected into one side of implanted tumors followed by exposure to ultrasound and laser radiation simultaneously for 5 minutes, during which infrared thermal images were obtained every minute. The results showed that the temperature elevation during the exposure was greatest for AuNDs-treated tumors, with the temperature reaching over 50 °C after 5 minutes of stimulation (Fig. 6c). In contrast, the temperatures measured in NDs- and AuMBs-treated tumors were only elevated to around 35 °C and 42 °C, respectively. Since infrared thermal imaging can only measure the surface temperature, we inserted a thermocouple into the tumor beneath the treatment site to record the intratumor temperature achieved during the treatment. Consistent with the results of infrared thermal imaging, treatment with AuNDs followed by exposure to ultrasound and laser radiation simultaneously could effectively and rapidly elevate the tumor temperature to over 50 °C. Moreover, treatment with either NDs or AuMBs followed by the same excitation method could not elevate the tumor temperature as effectively as when using AuNDs. Together these data indicate that the thermal effect of photothermal therapy was successfully enhanced by applying AuNDs to the tumor followed by exposure to ultrasound and laser radiation simultaneously. Under such treatment, the temperature was sufficiently elevated to cause irreversible thermal damage to the tumor and thus increase the probability of enhancing the photothermal therapeutic efficiency. The enhancement of both the cavitation and thermal effects suggests that enhanced sonoporation is also possible in in vivo treatment.

Bottom Line: This study used nanodroplets to significantly enhance the effectiveness of sonoporation relative to using conventional microbubbles.Enhanced cavitation also leads to significant enhancement of the sonoporation effects.Our in vivo results show that nanodroplet-vaporization-assisted sonoporation can increase the treatment temperature by more than 10 °C above that achieved by microbubble-based sonoporation.

View Article: PubMed Central - PubMed

Affiliation: National Taiwan University, Graduate Institute of Biomedical Electronics and Bioinformatics, Taipei 106, Taiwan.

ABSTRACT
Sonoporation refers to the use of ultrasound and acoustic cavitation to temporarily enhance the permeability of cellular membranes so as to enhance the delivery efficiency of therapeutic agents into cells. Microbubble-based ultrasound contrast agents are often used to facilitate these cavitation effects. This study used nanodroplets to significantly enhance the effectiveness of sonoporation relative to using conventional microbubbles. Significant enhancements were demonstrated both in vitro and in vivo by using gold nanorods encapsulated in nanodroplets for implementing plasmonic photothermal therapy. Combined excitation by ultrasound and laser radiation is used to trigger the gold nanodroplets to induce a liquid-to-gas phase change, which induces cavitation effects that are three-to-fivefold stronger than when using conventional microbubbles. Enhanced cavitation also leads to significant enhancement of the sonoporation effects. Our in vivo results show that nanodroplet-vaporization-assisted sonoporation can increase the treatment temperature by more than 10 °C above that achieved by microbubble-based sonoporation.

No MeSH data available.


Related in: MedlinePlus