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 s. 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.
Highlights
Given the limitations of passive diffusion through the plasma membrane, the ability to deliver therapeutic doses of drugs or other compounds to the interior of cells in the body is an important goal for many treatment strategies, including cancer treatment and gene therapy [1]
Visual inspection of uncoated bubbles using brightfield microscopy showed the bubbles to be spherical in appearance, and image analysis using the ImageJ measurement tool [44] revealed them to be homogeneous in diameter (5.08 μm ± SD of 1.57, N = 30) at a given focal plane (Fig. 2c)
We decided to explore the potential for ultrasound-activated microbubble drug delivery as an alternative intravesical treatment for urinary tract infection (UTI)
Summary
Given the limitations of passive diffusion through the plasma membrane, the ability to deliver therapeutic doses of drugs or other compounds to the interior of cells in the body is an important goal for many treatment strategies, including cancer treatment and gene therapy [1]. Chronic bacterial infection is a particular problem that would benefit from a penetrative drug delivery system, as it can involve intracellular infection [2], or poorly permeable biofilms that are difficult to treat with traditional antibiotics, especially on indwelling devices such as stents or catheters [3]. Urinary tract infection (UTI) is a good example of a chronic infection in need of improved, penetrative treatment modalities. There is evidence that a chronic form of lowlevel UTI plagues some patients, the elderly, causing less traditional but distressing lower urinary tract symptoms including incontinence [9,10,11]. UTI is one of the most prevalent hospital-acquired infections [12], and can lead to more serious complications including kidney infection and urosepsis [13,14]
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