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Ultrasound-activated microbubbles as a novel intracellular drug delivery system for urinary tract infection

Ultrasound-activated microbubbles as a novel intracellular drug delivery system for urinary tract infection
Ultrasound-activated microbubbles as a novel intracellular drug delivery system for urinary tract infection
The development of new modalities for high-efficiency intracellular drug delivery is a priority for a number of disease areas. One such area is urinary tract infection (UTI), which is one of the most common infectious diseases globally and which imposes an immense economic and healthcare burden. Common uropathogenic bacteria have been shown to invade the urothelial wall during acute UTI, forming latent intracellular reservoirs that can evade antimicrobials and the immune response. This behaviour likely facilitates the high recurrence rates after oral antibiotic treatments, which are not able to penetrate the bladder wall and accumulate to an effective concentration. Meanwhile, oral antibiotics may also exacerbate antimicrobial resistance and cause systemic side effects. Using a human urothelial organoid model, we tested the ability of novel ultrasound-activated lipid microbubbles to deliver drugs into the cytoplasm of apical cells. The gas-filled lipid microbubbles were decorated with liposomes containing the non-cell-permeant antibiotic gentamicin and a fluorescent marker. The microbubble suspension was added to buffer at the apical surface of the bladder model before being exposed to ultrasound (1.1 MHz, 2.5 Mpa, 5500 cycles at 20 ms pulse duration) for 20 seconds. Our results show that ultrasound-activated intracellular delivery using microbubbles was over 16 times greater than the control group and twice that achieved by liposomes that were not associated with microbubbles. Moreover, no cell damage was detected. Together, our data show that ultrasound-activated microbubbles can safely deliver high concentrations of drugs into urothelial cells, and have the potential to be a more efficacious alternative to traditional oral antibiotic regimes for UTI. This modality of intracellular drug delivery may prove useful in other clinical indications, such as cancer and gene therapy, where such penetration would aid in treatment.
0168-3659
166-175
Horsley, Harry
3ef8fa63-32a7-4725-8b40-29a708e8d978
Owen, Joshua
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Browning, Richard J.
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Carugo, Dario
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Malone-Lee, James
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Stride, Eleanor
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Rohn, Jennifer L.
b3cabf19-18c0-406a-8347-fb3759c7118b
Horsley, Harry
3ef8fa63-32a7-4725-8b40-29a708e8d978
Owen, Joshua
4e7fc6bc-f2c5-4622-894f-9e811eca84cd
Browning, Richard J.
32d183de-738d-49d7-8e74-af7b0a18e73f
Carugo, Dario
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Malone-Lee, James
46e0d42d-f286-41e0-9071-9bd37cf1c216
Stride, Eleanor
c0143e95-81fa-47c8-b9bc-5b4fc319bba6
Rohn, Jennifer L.
b3cabf19-18c0-406a-8347-fb3759c7118b

Horsley, Harry, Owen, Joshua, Browning, Richard J., Carugo, Dario, Malone-Lee, James, Stride, Eleanor and Rohn, Jennifer L. (2019) Ultrasound-activated microbubbles as a novel intracellular drug delivery system for urinary tract infection. Journal of Controlled Release, 301, 166-175. (doi:10.1016/j.jconrel.2019.03.017).

Record type: Article

Abstract

The development of new modalities for high-efficiency intracellular drug delivery is a priority for a number of disease areas. One such area is urinary tract infection (UTI), which is one of the most common infectious diseases globally and which imposes an immense economic and healthcare burden. Common uropathogenic bacteria have been shown to invade the urothelial wall during acute UTI, forming latent intracellular reservoirs that can evade antimicrobials and the immune response. This behaviour likely facilitates the high recurrence rates after oral antibiotic treatments, which are not able to penetrate the bladder wall and accumulate to an effective concentration. Meanwhile, oral antibiotics may also exacerbate antimicrobial resistance and cause systemic side effects. Using a human urothelial organoid model, we tested the ability of novel ultrasound-activated lipid microbubbles to deliver drugs into the cytoplasm of apical cells. The gas-filled lipid microbubbles were decorated with liposomes containing the non-cell-permeant antibiotic gentamicin and a fluorescent marker. The microbubble suspension was added to buffer at the apical surface of the bladder model before being exposed to ultrasound (1.1 MHz, 2.5 Mpa, 5500 cycles at 20 ms pulse duration) for 20 seconds. Our results show that ultrasound-activated intracellular delivery using microbubbles was over 16 times greater than the control group and twice that achieved by liposomes that were not associated with microbubbles. Moreover, no cell damage was detected. Together, our data show that ultrasound-activated microbubbles can safely deliver high concentrations of drugs into urothelial cells, and have the potential to be a more efficacious alternative to traditional oral antibiotic regimes for UTI. This modality of intracellular drug delivery may prove useful in other clinical indications, such as cancer and gene therapy, where such penetration would aid in treatment.

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JCR-D-18-01954R1-accepted - Accepted Manuscript
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Accepted/In Press date: 18 March 2019
e-pub ahead of print date: 20 March 2019
Published date: 10 May 2019

Identifiers

Local EPrints ID: 429322
URI: http://eprints.soton.ac.uk/id/eprint/429322
ISSN: 0168-3659
PURE UUID: 0451368c-3284-4a0b-9232-943f9d87ad90

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Date deposited: 26 Mar 2019 17:30
Last modified: 26 Nov 2021 06:28

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Contributors

Author: Harry Horsley
Author: Joshua Owen
Author: Richard J. Browning
Author: Dario Carugo
Author: James Malone-Lee
Author: Eleanor Stride
Author: Jennifer L. Rohn

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