One of the most common types of bone cancer is osteosarcoma, a malignant cancer that primarily affects children and young adults. Treatment typically involves high-dose chemotherapy and radiation, often used in combination. However, despite this therapy, the survival rate has not significantly improved since the 1970s. As a result, many researchers are striving to find alternative treatments. In this pursuit, a research team from Aston University has developed gallium-doped bioactive glasses that selectively kill over 99% of bone cancer cells.

Osteosarcoma treatment, like most cancer therapies, aims to destroy the tumor and prevent recurrence. However, the aftereffects of treatment often lead to bone mass deficits, eventually causing fractures. This highlights the need for another goal: bone restoration. Bioactive glasses, already used in bone formation, bind to bone and release calcium, phosphorus, and silicon. Now, researchers are designing these glasses to release therapeutic ions.

Richard Martin and his colleagues hypothesize that doping bioactive glasses with gallium ions can solve two problems: preventing cancer recurrence and reducing the risk of fractures. The team is designing a novel biomaterial that will act as targeted drug delivery to tumors while introducing regenerative ions to enhance new bone growth.

Gallium is toxic by nature, but when introduced to metabolically active cancer cells—which absorb all types of nutrients, including toxic ions—it inhibits bone resorption, crucial for bone cancer patients with lower bone density.

The researchers began by fabricating six types of silicate-based bioactive glasses, incorporating varying amounts of gallium oxide (Ga2O3) from 0 to 5 mol%. These glasses were ground into powders with particle sizes ranging from 40 to 63 µm.

Martin highlighted gallium as an ideal choice due to its stability in simple molecular forms. He explained that complex organic molecules wouldn’t withstand the high temperatures used to produce bioactive glasses, but gallium oxide can be easily integrated.

To evaluate the cytotoxicity of the gallium-doped glasses on cancer cells, the team created "conditioned media" by incubating the glass particles in cell culture media at concentrations of 10 or 20 mg/mL. After 24 hours, the particles were filtered out, leaving various concentrations of gallium ions in the media.

The conditioned media from the six gallium-doped powders were then tested on osteosarcoma cells, with normal osteoblasts as controls. Cell viability assays showed significant toxicity to cancer cells, with viability decreasing as gallium concentration increased.

After 10 days, osteosarcoma cells exposed to media conditioned with 10 mg/mL of glass containing 4% and 5% gallium showed reduced viability, approximately 60% and less than 10%, respectively. At a concentration of 20 mg/mL, the glass with 4% and 5% gallium caused 60% and over 99% cell death, respectively.

In contrast, gallium-free bioactive glass did not significantly affect cell viability, confirming that the cytotoxicity was due to the gallium rather than other glass components like calcium, sodium, phosphorus, or silicate ions.

While the gallium-doped glasses were more lethal to osteosarcoma cells than to normal osteoblasts, some toxicity was observed in control cells. Martin believes this slight toxicity is within safe limits, particularly since localized treatment would reduce side effects compared to orally administered gallium.

Further testing is needed to confirm the safety of these materials, though initial studies suggest that gallium-doped bioactive glasses are non-toxic in vivo and do not affect major organs like the liver or kidneys.

The team also conducted live/dead assays, confirming the gallium-doped glass had a potent cytotoxic effect on cancer cells with minimal harm to normal cells. Additionally, gallium exposure significantly reduced cancer cell proliferation and migration.

To study the effects on bone healing, the team introduced the glass to simulated body fluid for seven days. After seven days, it was observed that the glasses released calcium and phosphorus ions.

FTIR and energy-dispersive X-ray spectroscopy revealed that ions had precipitated onto the glass surface, forming an amorphous calcium phosphate or hydroxyapatite layer, signaling the early stages of bone regeneration. For clinical applications, the glass particles could be made into a paste and injected into the space left after tumor removal. This bioactivity would promote new bone growth, helping to prevent bone loss and fractures, according to Martin and his team. They concluded that gallium-doped bioactive glasses hold significant promise for bone grafting in osteosarcoma cases.

The next step is to test these materials on a broader range of bone cancers to confirm their effectiveness against different cancer types, while refining the dosage and delivery methods before proceeding to preclinical trials.

Reference:

1. Freeman, T. (2024, September 19). Gallium-doped bioactive glass kills 99% of bone cancer cells – Physics World. Physics World. https://physicsworld.com/a/gallium-doped-bioactive-glass-kills-99-of-bone-cancer-cells/

2. Hanaei1, Shirin B, Raghavan C Murugesan1, Lucas P Souza1, Juan I Cadiz-Miranda1, Lee Jeys2, Ivan B Wall3, Richard A Martin1, et al. “IOPscience.” Biomedical Materials, July 29, 2024. https://iopscience.iop.org/article/10.1088/1748-605X/ad76f1.

(Input from various sources)

(Rehash/Yash Kamble/MSM)