Efficacy optimization of low frequency microbubble-mediated sonoporation as a drug delivery platform to cancer cells
Ultrasound insonation of microbubbles can be used to form pores in cell membranes and facilitate the local trans-membrane transport of drugs and genes. An important factor in efficient delivery is the size of the delivered target compared to the generated membrane pores. Large molecule delivery rema...
| Main Authors: | , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2022-12-01
|
| Series: | International Journal of Pharmaceutics: X |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2590156722000214 |
| _version_ | 1798000453201428480 |
|---|---|
| author | Michal Eck Ramona Aronovich Tali Ilovitsh |
| author_facet | Michal Eck Ramona Aronovich Tali Ilovitsh |
| author_sort | Michal Eck |
| collection | DOAJ |
| description | Ultrasound insonation of microbubbles can be used to form pores in cell membranes and facilitate the local trans-membrane transport of drugs and genes. An important factor in efficient delivery is the size of the delivered target compared to the generated membrane pores. Large molecule delivery remains a challenge, and can affect the resulting therapeutic outcomes. To facilitate large molecule delivery, large pores need to be formed. While ultrasound typically uses megahertz frequencies, it was recently shown that when microbubbles are excited at a frequency of 250 kHz (an order of magnitude below the resonance frequency of these agents), their oscillations are significantly enhanced as compared to the megahertz range. Here, to promote the delivery of large molecules, we suggest using this low frequency and inducing large pore formation through the high-amplitude oscillations of microbubbles. We assessed the impact of low frequency microbubble-mediated sonoporation on breast cancer cell uptake by optimizing the delivery of 4 fluorescent molecules ranging from 1.2 to 70 kDa in size. The optimal ultrasound peak negative pressure was found to be 500 kPa. Increasing the pressure did not enhance the fraction of fluorescent cells, and in fact reduced cell viability. For the smaller molecule sizes, 1.2 kDa and 4 kDa, the groups treated with an ultrasound pressure of 500 kPa and MB resulted in a fraction of 58% and 29% of fluorescent cells respectively, whereas delivery of 20 kDa and 70 kDa molecules yielded 10% and 5%, respectively. These findings suggest that low-frequency (e.g., 250 kHz) insonation of microbubbles results in high amplitude oscillation in vitro that increase the uptake of large molecules. Successful ultrasound-mediated molecule delivery requires the careful selection of insonation parameters to maximize the therapeutic effect by increasing cell uptake. |
| first_indexed | 2024-04-11T11:20:30Z |
| format | Article |
| id | doaj.art-4e87ba81b14d42fda893d53b2df0af4b |
| institution | Directory Open Access Journal |
| issn | 2590-1567 |
| language | English |
| last_indexed | 2024-04-11T11:20:30Z |
| publishDate | 2022-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | International Journal of Pharmaceutics: X |
| spelling | doaj.art-4e87ba81b14d42fda893d53b2df0af4b2022-12-22T04:27:06ZengElsevierInternational Journal of Pharmaceutics: X2590-15672022-12-014100132Efficacy optimization of low frequency microbubble-mediated sonoporation as a drug delivery platform to cancer cellsMichal Eck0Ramona Aronovich1Tali Ilovitsh2Department of Biomedical Engineering, Tel Aviv University, Tel Aviv 6997801, IsraelDepartment of Biomedical Engineering, Tel Aviv University, Tel Aviv 6997801, IsraelCorresponding author at: Department of Biomedical Engineering, The Sagol School of Neuroscience, Tel Aviv University, Tel Aviv 6997801, Israel.; Department of Biomedical Engineering, Tel Aviv University, Tel Aviv 6997801, IsraelUltrasound insonation of microbubbles can be used to form pores in cell membranes and facilitate the local trans-membrane transport of drugs and genes. An important factor in efficient delivery is the size of the delivered target compared to the generated membrane pores. Large molecule delivery remains a challenge, and can affect the resulting therapeutic outcomes. To facilitate large molecule delivery, large pores need to be formed. While ultrasound typically uses megahertz frequencies, it was recently shown that when microbubbles are excited at a frequency of 250 kHz (an order of magnitude below the resonance frequency of these agents), their oscillations are significantly enhanced as compared to the megahertz range. Here, to promote the delivery of large molecules, we suggest using this low frequency and inducing large pore formation through the high-amplitude oscillations of microbubbles. We assessed the impact of low frequency microbubble-mediated sonoporation on breast cancer cell uptake by optimizing the delivery of 4 fluorescent molecules ranging from 1.2 to 70 kDa in size. The optimal ultrasound peak negative pressure was found to be 500 kPa. Increasing the pressure did not enhance the fraction of fluorescent cells, and in fact reduced cell viability. For the smaller molecule sizes, 1.2 kDa and 4 kDa, the groups treated with an ultrasound pressure of 500 kPa and MB resulted in a fraction of 58% and 29% of fluorescent cells respectively, whereas delivery of 20 kDa and 70 kDa molecules yielded 10% and 5%, respectively. These findings suggest that low-frequency (e.g., 250 kHz) insonation of microbubbles results in high amplitude oscillation in vitro that increase the uptake of large molecules. Successful ultrasound-mediated molecule delivery requires the careful selection of insonation parameters to maximize the therapeutic effect by increasing cell uptake.http://www.sciencedirect.com/science/article/pii/S2590156722000214FUSLow frequencyMicrobubblesSonoporationDrug delivery |
| spellingShingle | Michal Eck Ramona Aronovich Tali Ilovitsh Efficacy optimization of low frequency microbubble-mediated sonoporation as a drug delivery platform to cancer cells International Journal of Pharmaceutics: X FUS Low frequency Microbubbles Sonoporation Drug delivery |
| title | Efficacy optimization of low frequency microbubble-mediated sonoporation as a drug delivery platform to cancer cells |
| title_full | Efficacy optimization of low frequency microbubble-mediated sonoporation as a drug delivery platform to cancer cells |
| title_fullStr | Efficacy optimization of low frequency microbubble-mediated sonoporation as a drug delivery platform to cancer cells |
| title_full_unstemmed | Efficacy optimization of low frequency microbubble-mediated sonoporation as a drug delivery platform to cancer cells |
| title_short | Efficacy optimization of low frequency microbubble-mediated sonoporation as a drug delivery platform to cancer cells |
| title_sort | efficacy optimization of low frequency microbubble mediated sonoporation as a drug delivery platform to cancer cells |
| topic | FUS Low frequency Microbubbles Sonoporation Drug delivery |
| url | http://www.sciencedirect.com/science/article/pii/S2590156722000214 |
| work_keys_str_mv | AT michaleck efficacyoptimizationoflowfrequencymicrobubblemediatedsonoporationasadrugdeliveryplatformtocancercells AT ramonaaronovich efficacyoptimizationoflowfrequencymicrobubblemediatedsonoporationasadrugdeliveryplatformtocancercells AT taliilovitsh efficacyoptimizationoflowfrequencymicrobubblemediatedsonoporationasadrugdeliveryplatformtocancercells |