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Targeting Cytotoxic Drugs to Tumors Using Microbubbles

Targeting Cytotoxic Drugs to Tumors Using Microbubbles

Targeting Cytotoxic Drugs to Tumors Using Microbubbles

Targeting Cytotoxic Drugs to Tumors Using Microbubbles

Microbubbles carry the anticancer drug to the site of the tumour. Antibodies attached to the microbubbles are attracted to the growth hormone found around cancer cells. Once in situ, an ultrasound device is used to burst the bubbles, releasing the drug. Credit: Dr Sunjie Ye, University of Leeds/Theranostics
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Cytotoxic cancer drugs used in chemotherapy can cause unpleasant side effects by damaging healthy cells. A preclinical study published in Theranostics demonstrates a new method for the targeted delivery of cancer drugs to tumors.

Why targeting cancer drugs is important

In the UK there are approximately 367,000 new cases of cancer per year, with cancer resulting in over a quarter of all UK deaths. As part of their treatment, 28% of cancer patients undergo chemotherapy. Chemotherapy drugs kill cancer cells but do not target them specifically, resulting in damage to healthy cells. This can lead to side effects such as hair loss, sickness, tiredness, digestive issues and increased risk of infection due to a reduction in white blood cells. These side effects can be upsetting and greatly impact a patient’s quality of life, which is why minimizing off-target effects is the focus of much research.

How microbubbles work

In a recent study, researchers investigated the effectiveness of microbubbles for targeted delivery of cancer drugs to tumors in a mouse model of colorectal cancer. Co-lead author of the study Dr Nicola Ingram, from the University of Leeds, says that this particular cancer was chosen as “colorectal cancer is the fourth most common cancer in the UK and as the population grows older, incidence of the disease is expected to rise. Because many patients are older, they are less tolerant of the side effects of some anti-cancer therapies. Highly targeted drug delivery will reduce those side effects.”

The microbubbles – phospholipid-shelled spheres, approximately half the size of a red blood cell – were targeted to vascular endothelial growth receptor 2 (VEGFR2) using anti-VEGFR2 antibodies. VEGFR2 is a tumor endothelial marker that is expressed at higher levels in tumors compared to healthy tissue. Small spheres called liposomes containing cancer drugs are attached to the microbubbles. Once the microbubbles become concentrated at the site of the tumor, the drug can be strategically released by applying ultrasound. This approach could reduce damage to healthy tissue, focusing the treatment by using ultrasound only at the site of the tumor. Dr Ingram explains, “Microbubbles have been used in diagnostics for decades, for example in the field of cardiology to show the narrowing of blood vessels. We are developing the next chapter of microbubble technology.”

In a press release, head of the Molecular and Nanoscale Physics Group at Leeds Professor Stephen Evans said, "The results of this study are exciting because we not only show the very precise and targeted way microbubbles can be guided to cancer sites but that the efficacy of drug delivery is substantially improved, opening the way to use highly toxic drugs to fight cancer, without the harmful side effects. Put simply: you get more bang for your buck."

Microbubbles targeting cancer

First, researchers tested the targeting ability of the microbubbles. It was shown in vitro that they bound to cells expressing VEGFR2 significantly more than cells that didn’t. Targeting was also tested in colorectal cancer tumors in mice by loading microbubbles with the bioluminescent chemical luciferin. Tumor bioluminescence was higher when VEGFR2-targeted microbubbles were used compared to non-targeted microbubbles. This indicated that VEGFR2-targeted microbubbles could effectively target tumors.

Microbubbles were then loaded with the colorectal cancer treatment irinotecan, which inhibits the enzyme topoisomerase I. This causes breaks in DNA, meaning cells cannot divide and eventually die. This is how the drug kills cancer cells, but as its mechanism is not exclusive to cancer cells, the drug can also damage healthy cells. The dose given to the mice was 2 mg/kg, 25 times lower than the standard therapeutic dose. Irinotecan microbubbles with ultrasound stimulation inhibited tumor growth by 50%, whereas irinotecan alone inhibited it by 38%. Irinotecan was also metabolized and excreted faster when administered alone. Levels of irinotecan in tumors 1 hour after treatment were the same as levels 72 hours after irinotecan microbubble treatment.

In the body, irinotecan is converted to SN38, which has shown promise in in vitro studies as an anti-cancer agent. However, SN38 is extremely toxic and cannot be dissolved in pharmaceutical solvents, preventing its clinical use to date. The researchers loaded microbubbles with SN38 to see if they could overcome these obstacles. Compared to microbubbles with no treatment, SN38 microbubbles reduced tumor masses and significantly slowed the rate of tumor growth. They also increased breaks in DNA and cell death within the tumors. The mice also showed no signs of SN38 toxicity, indicating that using microbubbles can minimize side effects of toxic drugs.

The study also demonstrated that the microbubbles required ultrasound to trigger drug release. This is important for limiting damage to healthy tissues, as the microbubbles were shown to bind to VEGFR2 in the liver, kidney, and spleen. Irinotecan microbubbles administered without ultrasound stimulation did not inhibit tumor growth. Irinotecan and SN38 were detected in tumors 72 hours after microbubble treatment plus ultrasound, but levels were undetectable after treatment without ultrasound.

What this study means for cancer treatment

These results indicate that microbubbles have the potential to increase the efficacy of cytotoxic drugs whilst reducing side effects when used as targeted delivery vehicles. Dr Ingram says that “The next phase of the research is to get the microbubbles manufactured to clinical standard and conduct a small-scale patient trial into the use of microbubbles to deliver anti-cancer agents to look at safety and tolerability as part of a Phase I clinical trial.”

Nicola Ingram was speaking with Francesca Benson.