Inhibition of melanoma by ultrasound-microbubble-aided drug delivery suggests membrane permeabilization

Abstract

Ultrasound exposure-induced cavitation has been shown to accentuate cell membrane permeability, thus promoting effective drug delivery into cells, a technique that can be enhanced in the presence of microbubbles (MB). Here we applied this method as a treatment for malignant melanoma of the eyelid. The incidence of malignant melanoma in ophthalmology is relatively high, but its treatment is cosmetically difficult. A greater in vitro growth suppression of B-16 melanoma cells was achieved using ultrasound and MB in combination with the anticancer drug bleomycin than when a more concentrated dose of bleomycin alone was applied to the cell culture. Moreover, this effect was enhanced in an in vivo tumor model created by injecting B-16 melanoma cells into the lower eyelids of SCID mice. The antitumor effect of bleomycin was observed at a lower dose (0.5 mg/ ml) when the treatment was used in conjunction with ultrasound. The effect was further enhanced when MB were included, with tumor shrinkage occurring at bleomycin levels of 0.06 mg/ml. These results show that ultrasound and MB promote efficient bleomycin uptake by cells, and that the technique is a potentially useful drug delivery method.

Nanoporous Platforms for Cellular Sensing and Delivery

“…For comparison, when bleomycin was delivered by electroporation, the bioavailability was improved only 2 to 10-fold [36,37], whereas the use of bleomycin-loaded microspheres did not improve the drug bioavailability when compared to free BLM [38]. Ultrasound application improved BLM bioavailability 8-fold, and the effect was enhanced 33 times when microbubbles were included in the treatment [39]. Finally, the use of liposomes for BLM delivery brought about 20 to 40-fold increase in bioavailability [40], resulting in a significant decrease in BLM-induced lung injury [41].…”

Mechanisms of Microbubble-Facilitated Sonoporation for Drug and Gene Delivery

“…Compared with conventional drug-delivery methods, such as intravenous injection or oral administration, targeted-drug delivery using ultrasound and microbubbles can substantially reduce undesirable systemic side effects. Compared with using the anti-cancer drug bleomycin alone, a combination of ultrasound and microbubbles successfully inhibited cancer cell growth at a much lower dosage, demonstrated by the shrinkage of tumor in an in vivo melanoma tumor model in mice [92]. For brain cancer treatment, the intact blood–brain barrier (BBB) often prevents cytotoxic levels of anticancer drugs such as doxorubicin (DOX) from being achieved.…”

Cell-penetrating and cell-targeting peptides in drug delivery

“…Sonication has been shown to improve the delivery efficacy of a cytotoxic agent, leading to a significant reduction of the injected dose [113]. However, if applied to small drugs, a rapid clearance from the blood stream can be expected, which will reduce the time window of the sonication effects.…”