Osteosarcoma, the most common type of bone tumour, is a highly malignant cancer that mainly affects children and young adults. Patients are typically treated with an aggressive combination of resection and chemotherapy, but survival rates have not improved significantly since the 1970s. With alternative therapies urgently needed, a research team at Aston University has developed a gallium-doped bioactive glass that selectively kills over 99% of bone cancer cells.
The main objective of osteosarcoma treatment is to destroy the tumour and prevent recurrence. But over half of long-term survivors are left with bone mass deficits that can lead to fractures, making bone restoration another important goal. Bioactive glasses are already used to repair and regenerate bone – they bond with bone tissue and induce bone formation by releasing ions such as calcium, phosphorus and silicon. But they can also be designed to release therapeutic ions.
Team leader Richard Martin and colleagues propose that bioactive glasses doped with gallium ions could address both tasks – helping to prevent cancer recurrence and lowering the risk of fracture. They designed a novel biomaterial that provides targeted drug delivery to the tumour site, while also introducing a regenerative scaffold to stimulate the new bone growth.
“Gallium is a toxic ion that has been widely studied and is known to be effective for cancer therapy. Cancer cells tend to be more metabolically active and therefore uptake more nutrients and minerals to grow – and this includes the toxic gallium ions,” Martin explains. “Gallium is also known to inhibit bone resorption, which is important as bone cancer patients tend to have lower bone density and are more prone to fractures.”
Glass design
Starting with a silicate-based bioactive glass, the researchers fabricated six glasses doped with between 0 and 5 mol% of gallium oxide (Ga2O3). They then ground the glasses into powders with a particle size between 40 and 63 µm.
Martin notes that gallium is a good choice for incorporating into the glass, as it is effective in a variety of simple molecular forms. “Complex organic molecules would not survive the high processing temperatures required to make bioactive glasses, whereas gallium oxide can be incorporated relatively easily,” he says.
To test the cytotoxic effects of the bioactive glasses on cancer cells, the team created “conditioned media”, by incubating the gallium-doped glass particles in cell culture media at concentrations of 10 or 20 mg/mL. After 24 h, the particles were filtered out to leave various levels of gallium ions in the media.
The researchers then exposed osteosarcoma cells, as well as normal osteoblasts as controls, to conditioned media from the six gallium-doped powders. Cell viability assays revealed significant cytotoxicity in cancer cells exposed to the conditioned media, with a reduction in cell viability correlating with gallium concentration.
After 10 days, cancer cells exposed to media conditioned with 10 mg/mL of 4 and 5% gallium-doped glass showed decreased cell viability, to roughly 60% and less than 10%, respectively. The 20 mg/mL of 4% and 5% gallium-doped glass were the most toxic to the cancer cells, causing 60% and more than 99% cell death, respectively, after 10 days.
Exposure to gallium-free bioglass did not significantly impact cell viability – confirming that the toxicity is due to gallium and not the other components of the glass (calcium, sodium, phosphorus and silicate ions).
While the glasses preferentially killed osteosarcoma cells compared with normal osteoblasts, some cytotoxic effects were also seen in the control cells. Martin believes that this slight toxicity to normal healthy cells is within safe limits, noting that the localized nature of the treatment should significantly reduce side effects compared with orally administered gallium.
“Further experiments are needed to confirm the safety of these materials,” he says, “but our initial studies show that these gallium-doped bioactive glasses are not toxic in vivo and have no effects on major organs such as the liver or kidneys.”
The researchers also performed live/dead assays on the osteosarcoma and control cells. The results confirmed the highly cytotoxic effect of gallium-doped bioactive glass on the cancer cells with relatively minor toxicity towards normal cells. They also found that exposure to the gallium-doped glass significantly reduced cancer cell proliferation and migration.
Bone regeneration
To test whether the bioactive glasses could also help to heal bone, the team exposed glass samples to simulated body fluid for seven days. Under these physiological conditions, the glasses gradually released calcium and phosphorous ions.
FTIR and energy dispersive X-ray spectroscopy revealed that these ions precipitated onto the glass surface to form an amorphous calcium phosphate/hydroxyapatite layer – indicating the initial stages of bone regeneration. For clinical use, the glass particles could be mixed into a paste and injected into the void created during tumour surgery.
“This bioactivity will help generate new bone formation and prevent bone mass deficits and potential future fractures,” Martin and colleagues conclude. “The results when combined strongly suggest that gallium-doped bioactive glasses have great potential for osteosarcoma-related bone grafting applications.”
Next, the team plans to test the materials on a wide range of bone cancers to ensure the treatment is effective against different cancer types, as well as optimizing the dosage and delivery before undertaking preclinical tests.
The researchers report their findings in Biomedical Materials.
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