Prolonging pulse duration in ultrasound-mediated gene delivery lowers acoustic pressure threshold for efficient gene transfer to cells and small animals
| Autor: | Shuxian Song, Dominic M. Tran, Jeremy Chen, James Harrang, Carol H. Miao, Bryn M. Smith |
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| Rok vydání: | 2018 |
| Předmět: |
Male
0301 basic medicine Time Factors Pharmaceutical Science Gene delivery Transfection Article Mice 03 medical and health sciences 0302 clinical medicine In vivo Pressure medicine Animals Humans Sound pressure Cell damage Ultrasonography Microbubbles Pulse (signal processing) business.industry Chemistry Ultrasound Gene Transfer Techniques Pulse duration Acoustics Genetic Therapy medicine.disease Mice Inbred C57BL HEK293 Cells 030104 developmental biology 030220 oncology & carcinogenesis business Biomedical engineering |
| Zdroj: | Journal of Controlled Release. 279:345-354 |
| ISSN: | 0168-3659 |
| DOI: | 10.1016/j.jconrel.2018.04.012 |
| Popis: | While ultrasound-mediated gene delivery (UMGD) has been accomplished using high peak negative pressures (PNPs) of 2 MPa or above, emerging research showed that this may not be a requirement for microbubble (MB) cavitation. Thus, we investigated lower-pressure conditions close to the MB inertial cavitation threshold and focused towards further increasing gene transfer efficiency and reducing associated cell damage. We created a matrix of 21 conditions (n = 3/cond.) to test in HEK293T cells using pulse durations spanning 18 μs–36 ms and PNPs spanning 0.5–2.5 MPa. Longer pulse duration conditions yielded significant increase in transgene expression relative to sham with local maxima between 20 J and 100 J energy curves. A similar set of 17 conditions (n = 4/cond.) was tested in mice using pulse durations spanning 18 μs–22 ms and PNPs spanning 0.5–2.5 MPa. We observed local maxima located between 1 J and 10 J energy curves in treated mice. Of these, several low pressure conditions showed a decrease in ALT and AST levels while maintaining better or comparable expression to our positive control, indicating a clear benefit to allow for effective transfection with minimized tissue damage versus the high-intensity control. Our data indicates that it is possible to eliminate the requirement of high PNPs by prolonging pulse durations for effective UMGD in vitro and in vivo, circumventing the peak power density limitations imposed by piezo-materials used in US transducers. Overall, these results demonstrate the advancement of UMGD technology for achieving efficient gene transfer and potential scalability to larger animal models and human application. |
| Databáze: | OpenAIRE |
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