Editors' ChoiceCancer

Therapeutic microbubbles make tumor cells pop

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Science Translational Medicine  23 Sep 2020:
Vol. 12, Issue 562, eabe6019
DOI: 10.1126/scitranslmed.abe6019

Abstract

Combining ultrasound release and molecular targeting selectively delivered extremely toxic and hydrophobic drugs to tumor cells.

An ongoing challenge in improving cancer treatment is the need to administer cytotoxic drugs while limiting side effects. Various advanced drug delivery systems have been developed to increase drug delivery to tumor cells and limit delivery to healthy tissues. Ingram et al. combined a tumor marker targeting strategy and an ultrasound-triggered drug release strategy to selectively deliver a highly toxic drug to tumor cells in mice. The authors had previously developed therapeutic microbubbles, which are able to remain in the intravascular space until “popped” with ultrasound waves. These microbubbles consist of a lipid monolayer bubble coated with much smaller, drug-containing liposomes. Although previous work showed that ultrasound could trigger release of these liposomes in vitro, the efficacy and biodistribution of delivered drugs in vivo were unknown.

In a series of experiments using a mouse model of colorectal cancer, the authors used therapeutic microbubbles to deliver a hydrophobic topoisomerase inhibitor (SN38) and its prodrug (irinotecan) to xenograft tumors. They performed extensive characterization of drug distribution, tumor inhibition, and cytotoxicity, comparing microbubble delivery to intravenous administration. Drug delivery to tumors was enhanced by ultrasound-triggered disruption of microbubbles. Even when colorectal cancer tumors were targeted with a vascular endothelial growth factor (VEGF) receptors antibody on the liposomes, ultrasound-triggered release was necessary to enhance drug delivery.

The authors were able to combine multiple tumor targeting strategies to selectively deliver an extremely toxic and hydrophobic drug to tumor cells. This series of experiments showed how drugs that were thought to be too toxic or too hydrophobic for in vivo use may be used in cancer therapy. Researchers are now able to selectively deliver hydrophobic and toxic drugs to tumors with minimal drug accumulation in surrounding healthy tissues. Although the results of these animal experiments are very promising, this combination of drug targeting strategies has not been tested in humans, and mechanistic details of drug delivery from liposomes to tumors in the presence of ultrasound waves remain unclear.

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